v2
latestOpenAPI 3.1.02026-07-3171165552.0 KBReference Check
Get Result
Retrieve reference check job status.
This allows both fetching the job result and polling for job completion.
Whilst the job is in progress its status will be either PENDING or STARTED.
Once the job is complete its status will be SUCCESS and the result can be read under the result key of this response.
get/reference_check/tasks/{task_id}
Path parameters
task_idstring required
Headers
authorizationstring
Set to Bearer <token> to pass token for authorization.
Set to Bearer <token> to pass token for authorization.
Response
Successful Response
Example response
{
"overallTally": {
"contradicting": 98,
"mentioning": 49577,
"supporting": 1027,
"total": 51417,
"unclassified": 715
},
"papers": {
"10.1002/hep.26015": {
"abstract": "Sphingolipids are important structural components of cell membranes and act as critical regulators of cell function by modulating intracellular signaling pathways. Specific sphingolipids, such as ceramide, glucosylceramide, and ganglioside GM3, have been implicated in various aspects of insulin resistance, because they have been shown to modify several steps in the insulin signaling pathway, such as phosphorylation of either protein kinase B (Akt) or of the insulin receptor. We now explore the role of the ceramide acyl chain length in insulin signaling by using a ceramide synthase 2 (CerS2) null mouse, which is unable to synthesize very long acyl chain (C22-C24) ceramides. CerS2 null mice exhibited glucose intolerance despite normal insulin secretion from the pancreas. Both insulin receptor and Akt phosphorylation were abrogated in liver, but not in adipose tissue or in skeletal muscle. The lack of insulin receptor phosphorylation in liver correlated with its inability to translocate into detergent-resistant membranes (DRMs). Moreover, DRMs in CerS2 null mice displayed properties significantly different from those in wild-type mice, suggesting that the altered sphingolipid acyl chain length directly affects insulin receptor translocation and subsequent signaling. Conclusion: We conclude that the sphingolipid acyl chain composition of liver regulates insulin signaling by modifying insulin receptor translocation into membrane microdomains. (HEPATOLOGY 2013;57:525-532)",
"authors": [
{
"affiliation": "Weizmann Institute of Science",
"affiliationID": "11815",
"affiliationSlug": "weizmann-institute-of-science-b3jp",
"authorID": "178208965",
"authorName": "Joo Won Park",
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"authorSlug": "joo-won-park-8GVygVM",
"family": "Park",
"given": "Joo Won"
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{
"affiliation": "Weizmann Institute of Science",
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"authorID": "13634490",
"authorName": "Woo Jae Park",
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"authorSlug": "woo-jae-park-9DXbrG",
"family": "Park",
"given": "Woo Jae"
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{
"affiliation": "Weizmann Institute of Science",
"affiliationID": "11815",
"affiliationSlug": "weizmann-institute-of-science-b3jp",
"authorID": "11463805",
"authorName": "Yael Kuperman",
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"authorSlug": "yael-kuperman-AGNLa3",
"family": "Kuperman",
"given": "Yael"
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{
"affiliation": "Weizmann Institute of Science",
"affiliationID": "11815",
"affiliationSlug": "weizmann-institute-of-science-b3jp",
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"authorName": "Sigalit Boura-Halfon",
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"authorSlug": "sigalit-boura-halfon-R5099",
"family": "Boura-Halfon",
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{
"affiliation": "Weizmann Institute of Science",
"affiliationID": "11815",
"affiliationSlug": "weizmann-institute-of-science-b3jp",
"authorID": "6235045",
"authorName": "Yael Pewzner-Jung",
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{
"affiliation": "Weizmann Institute of Science",
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"authorName": "Anthony H. Futerman",
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"family": "Futerman",
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"doi": "10.1002/hep.26015",
"editorialNotices": [],
"id": 50524713,
"issns": [
"0270-9139"
],
"issue": "2",
"journal": "Hepatology",
"journalSlug": "5GEpG",
"keywords": [
"Steatohepatitis/Metabolic Liver Disease"
],
"memberId": 311,
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"article"
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"shortJournal": "Hepatology",
"slug": "ablation-of-very-long-acyl-GA16lb",
"title": "Ablation of very long acyl chain sphingolipids causes hepatic insulin resistance in mice due to altered detergent-resistant membranes",
"type": "journal-article",
"volume": "57",
"year": 2012
},
"10.1002/ijc.21422": {
"abstract": "Monocytes are recruited into tumors from the circulation along defined chemotactic gradients and they then differentiate into tumor-associated macrophages (TAMs). Recent evidence has shown that large numbers of TAMs are attracted to and retained in avascular and necrotic areas, where they are exposed to tumor hypoxia. At these sites, TAMs appear to undergo marked phenotypic changes with activation of hypoxia-inducible transcription factors, dramatically upregulating the expression of a large number of genes encoding mitogenic, proangiogenic and prometastatic cytokines and enzymes. As a consequence, high TAMs density has been correlated with increased tumor growth and angiogenesis in various tumor types. Since hypoxia is a hallmark feature of malignant tumors and hypoxic tumor cells are relatively resistant to radio-and chemotherapy, these areas have become a target for novel forms of anticancer therapy. These include hypoxiatargeted gene therapy in which macrophages are armed with therapeutic genes that are activated by hypoxia-responsive promoter elements. This restricts transgene expression to hypoxic areas, where the gene product is then released and acts on neighboring hypoxic tumor cells or proliferating blood vessels. In this way, the responses of macrophages to tumor hypoxia can be exploited to deliver potent antitumor agents to these poorly vascularized, and thus largely inaccessible, areas of tumors. ' 2005 Wiley-Liss, Inc.",
"authors": [
{
"affiliation": "University of Sheffield",
"affiliationID": "10452",
"affiliationSlug": "university-of-sheffield-MzKE",
"authorID": "10326446",
"authorName": "Craig Murdoch",
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{
"affiliation": "University of Sheffield",
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"authorName": "Claire E. Lewis",
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"id": 50587440,
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"0020-7136",
"1097-0215"
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"issue": "5",
"journal": "International Journal of Cancer",
"journalSlug": "ej5Qr",
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"macrophage",
"tumor-associated macrophages (TAMs)",
"angiogenesis",
"hypoxia",
"tumor"
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"page": "701-708",
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"shortJournal": "Int. J. Cancer",
"slug": "macrophage-migration-and-gene-expression-L6MNGQ",
"title": "Macrophage migration and gene expression in response to tumor hypoxia",
"type": "journal-article",
"volume": "117",
"year": 2005
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"10.1006/bmmb.1993.1059": {
"authors": [
{
"affiliation": "City Of Hope National Medical Center",
"affiliationID": "1813",
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"authorID": "38973486",
"authorName": "D E Comings",
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"authorSlug": "d-e-comings-434RjY",
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"family": "Flanagan",
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"authorID": "27998969",
"authorName": "George Dietz",
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"doi": "10.1006/bmmb.1993.1059",
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"id": 52091767,
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"0885-4505"
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"issue": "2",
"journal": "Biochemical Medicine and Metabolic Biology",
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"slug": "the-dopamine-d2-receptor-drd2-JMkQkY",
"title": "The Dopamine D2 Receptor (DRD2) as a Major Gene in Obesity and Height",
"type": "journal-article",
"volume": "50",
"year": 1993
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"10.1007/s00125-005-1735-1": {
"authors": [
{
"affiliation": "University of Tokyo",
"affiliationID": "11716",
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"authorID": "8690074",
"authorName": "Nobuhiro Shojima",
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{
"affiliation": "Tohoku University",
"affiliationID": "11040",
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"authorID": "211303337",
"authorName": "Takehide Ogihara",
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{
"affiliation": "Saitama Medical University",
"affiliationID": "18641",
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"authorID": "8346999",
"authorName": "Kouichi Inukai",
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"authorSlug": "kouichi-inukai-ePApMm",
"family": "Inukai",
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"affiliation": "University of Tokyo",
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"authorID": "78480766",
"authorName": "Midori Fujishiro",
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"affiliation": "University of Tokyo",
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"authorID": "12700981",
"authorName": "Hideyuki Sakoda",
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"affiliation": "University of Tokyo",
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"authorID": "6124749",
"authorName": "Akifumi Kushiyama",
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"affiliation": "Tohoku University",
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"authorID": "80950237",
"authorName": "Hideki Katagiri",
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"authorID": "6063891",
"authorName": "Motonobu Anai",
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"authorName": "Hiraku Ono",
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"authorSlug": "hiraku-ono-xxMAJw",
"family": "Ono",
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{
"affiliation": "University of Tokyo",
"affiliationID": "11716",
"affiliationSlug": "university-of-tokyo-QYyz",
"authorID": "20980323",
"authorName": "Yasushi Fukushima",
"authorSequenceNumber": 10,
"authorSlug": "yasushi-fukushima-JlrVd0",
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"affiliation": "University of Tokyo",
"affiliationID": "11716",
"affiliationSlug": "university-of-tokyo-QYyz",
"authorID": "6301718",
"authorName": "Nanao Horike",
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"authorSlug": "nanao-horike-dvEwXj",
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{
"affiliation": "University of Tokyo",
"affiliationID": "11716",
"affiliationSlug": "university-of-tokyo-QYyz",
"authorID": "7408258",
"authorName": "Amelia Y.I. Viana",
"authorSequenceNumber": 12,
"authorSlug": "amelia-y-i-viana-gZzzwK",
"family": "Viana",
"given": "Amelia Y.I."
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{
"affiliation": "University of Tokyo",
"affiliationID": "11716",
"affiliationSlug": "university-of-tokyo-QYyz",
"authorID": "5464422",
"authorName": "Yasunobu Uchijima",
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"authorSlug": "yasunobu-uchijima-xXYWkb",
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{
"affiliation": "University of Tokyo",
"affiliationID": "11716",
"affiliationSlug": "university-of-tokyo-QYyz",
"authorID": "16077383",
"authorName": "Hiroki Kurihara",
"authorSequenceNumber": 14,
"authorSlug": "hiroki-kurihara-a82d9j",
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{
"affiliation": "University of Tokyo",
"affiliationID": "11716",
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"authorID": "15656692",
"authorName": "Tomoichiro Asano",
"authorSequenceNumber": 15,
"authorSlug": "tomoichiro-asano-WnKyEw",
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],
"doi": "10.1007/s00125-005-1735-1",
"editorialNotices": [],
"id": 59412464,
"issns": [
"0012-186X",
"1432-0428"
],
"issue": "5",
"journal": "Diabetologia",
"journalSlug": "PQL9g",
"memberId": 297,
"normalizedTypes": [
"article"
],
"page": "984-992",
"preprintLinks": [],
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"publisher": "Springer Science and Business Media LLC",
"retracted": false,
"shortJournal": "Diabetologia",
"slug": "serum-concentrations-of-resistin-like-molecules-y5KM3l",
"title": "Serum concentrations of resistin-like molecules β and γ are elevated in high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bone marrow",
"type": "journal-article",
"volume": "48",
"year": 2005
},
"10.1007/s00125-013-2846-8": {
"abstract": "Aims/hypothesis Metabolic disorders are commonly investigated using knockout and transgenic mouse models. A variety of mouse strains have been used for this purpose. However, mouse strains can differ in their inherent propensities to develop metabolic disease, which may affect the experimental outcomes of metabolic studies. We have investigated straindependent differences in the susceptibility to diet-induced obesity and insulin resistance in five commonly used inbred mouse strains (C57BL/6J, 129X1/SvJ, BALB/c, DBA/2 and FVB/N). Methods Mice were fed either a low-fat or a high-fat diet (HFD) for 8 weeks. Whole-body energy expenditure and body composition were then determined. Tissues were used to measure markers of mitochondrial metabolism, inflammation, oxidative stress and lipid accumulation. Results BL6, 129X1, DBA/2 and FVB/N mice were all susceptible to varying degrees to HFD-induced obesity, glucose intolerance and insulin resistance, but BALB/c mice exhibited some protection from these detrimental effects. This protection could not be explained by differences in mitochondrial metabolism or oxidative stress in liver or muscle, or inflammation in adipose tissue. Interestingly, in contrast with the other strains, BALB/c mice did not accumulate excess lipid (triacylglycerols and diacylglycerols) in the liver; this is potentially related to lower fatty acid uptake rather than differences in lipogenesis or lipid oxidation. Conclusions/interpretation Collectively, our findings indicate that most mouse strains develop metabolic defects on an HFD. However, there are inherent differences between strains, and thus the genetic background needs to be considered carefully in metabolic studies. \nKeywords",
"authors": [
{
"affiliation": "Garvan Institute of Medical Research",
"affiliationID": "18807",
"affiliationSlug": "garvan-institute-of-medical-research-Y0EG",
"authorID": "18166098",
"authorName": "Magdalene K. Montgomery",
"authorSequenceNumber": 1,
"authorSlug": "magdalene-k-montgomery-6JAODr",
"family": "Montgomery",
"given": "Magdalene K."
},
{
"affiliation": "Garvan Institute of Medical Research",
"affiliationID": "18807",
"affiliationSlug": "garvan-institute-of-medical-research-Y0EG",
"authorID": "97047997",
"authorName": "Nicole L Hallahan",
"authorSequenceNumber": 2,
"authorSlug": "nicole-l-hallahan-vvrjdV",
"family": "Hallahan",
"given": "Nicole L"
},
{
"affiliation": "University of Wollongong",
"affiliationID": "20782",
"affiliationSlug": "university-of-wollongong-VWYO",
"authorID": "17560038",
"authorName": "Simon H. J. Brown",
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"authorSlug": "simon-h-j-brown-VyPjvM",
"family": "Brown",
"given": "Simon H. J."
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{
"affiliation": "Garvan Institute of Medical Research",
"affiliationID": "18807",
"affiliationSlug": "garvan-institute-of-medical-research-Y0EG",
"authorID": "52122459",
"authorName": "Menghan Liu",
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"authorSlug": "menghan-liu-bnvKEW",
"family": "Liu",
"given": "Menghan"
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{
"affiliation": "University of Wollongong",
"affiliationID": "20782",
"affiliationSlug": "university-of-wollongong-VWYO",
"authorID": "18720972",
"authorName": "Todd W. Mitchell",
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"family": "Mitchell",
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{
"affiliation": "Garvan Institute of Medical Research",
"affiliationID": "18807",
"affiliationSlug": "garvan-institute-of-medical-research-Y0EG",
"authorID": "8713947",
"authorName": "Gregory J. Cooney",
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"family": "Cooney",
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{
"affiliation": "Garvan Institute of Medical Research",
"affiliationID": "18807",
"affiliationSlug": "garvan-institute-of-medical-research-Y0EG",
"authorID": "66870151",
"authorName": "Nigel Turner",
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],
"doi": "10.1007/s00125-013-2846-8",
"editorialNotices": [],
"id": 59415386,
"issns": [
"0012-186X",
"1432-0428"
],
"issue": "5",
"journal": "Diabetologia",
"journalSlug": "PQL9g",
"memberId": 297,
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"page": "1129-1139",
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"publisher": "Springer Science and Business Media LLC",
"retracted": false,
"shortJournal": "Diabetologia",
"slug": "mouse-strain-dependent-variation-in-obesity-4X12WV",
"title": "Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding",
"type": "journal-article",
"volume": "56",
"year": 2013
},
"10.1007/s11892-008-0032-z": {
"abstract": "Ectopic fat is defined by the deposition of triglycerides within cells of non-adipose tissue that normally contain only small amounts of fat. Over the past decade, magnetic resonance spectroscopy has been used extensively for noninvasive quantification of intramyocellular, intrahepatocellular, and more recently myocardial and pancreatic lipids. In liver and muscle, triglyceride content usually correlates with whole-body and tissue-specific insulin sensitivity. However, fat mass and oxidative capacity influence this relationship, indicating that ectopic lipid content is not the only factor that explains insulin resistance. Ectopic lipids may rather serve as biomarkers of the balance between metabolic supply and demand in different states of insulin sensitivity. Consequently, ectopic lipid concentrations, particularly in the liver, decrease with lifestyle- or drug-induced improvement of insulin sensitivity.",
"authors": [
{
"affiliation": "Hanusch Hospital",
"affiliationID": "197271",
"affiliationSlug": "hanusch-hospital-NM0w9",
"authorID": "11468441",
"authorName": "Angelika Lettner",
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"authorSlug": "angelika-lettner-X4eL6k",
"family": "Lettner",
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{
"affiliation": "Hanusch Hospital",
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"authorID": "144668417",
"authorName": "Michael Roden",
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],
"doi": "10.1007/s11892-008-0032-z",
"editorialNotices": [],
"id": 61188900,
"issns": [
"1534-4827",
"1539-0829"
],
"issue": "3",
"journal": "Current Diabetes Reports",
"journalSlug": "jMJGJ",
"memberId": 297,
"normalizedTypes": [
"article"
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"page": "185-191",
"preprintLinks": [],
"publicationLinks": [],
"publisher": "Springer Science and Business Media LLC",
"retracted": false,
"shortJournal": "Curr Diab Rep",
"slug": "ectopic-fat-and-insulin-resistance-3g5eOO",
"title": "Ectopic fat and insulin resistance",
"type": "journal-article",
"volume": "8",
"year": 2008
},
"10.1016/j.cell.2012.02.017": {
"abstract": "Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance.",
"authors": [
{
"affiliation": "Yale University",
"affiliationID": "8068",
"affiliationSlug": "yale-university-kyQE",
"authorID": "10373696",
"authorName": "Varman T. Samuel",
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"authorSlug": "varman-t-samuel-M2rnek",
"family": "Samuel",
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{
"affiliation": "Yale University",
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"authorName": "Gerald I. Shulman",
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"doi": "10.1016/j.cell.2012.02.017",
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"id": 67157549,
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"0092-8674"
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"issue": "5",
"journal": "Cell",
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"shortJournal": "Cell",
"slug": "mechanisms-for-insulin-resistance-common-Aazynv",
"title": "Mechanisms for Insulin Resistance: Common Threads and Missing Links",
"type": "journal-article",
"volume": "148",
"year": 2012
},
"10.1016/j.cell.2014.03.066": {
"abstract": "SUMMARY\nBeige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13 and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat. Mechanistically, macrophages recruited to cold-stressed subcutaneous white adipose tissue (scWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production, factors required for browning of scWAT. Conversely, administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity. Together, our findings have uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its targeting to treat obesity.",
"authors": [
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "32615577",
"authorName": "Yifu Qiu",
"authorSequenceNumber": 1,
"authorSlug": "yifu-qiu-n15v8D",
"family": "Qiu",
"given": "Yifu"
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "19867627",
"authorName": "Khoa D. Nguyen",
"authorSequenceNumber": 2,
"authorSlug": "khoa-d-nguyen-N802GN",
"family": "Nguyen",
"given": "Khoa D."
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "5895306",
"authorName": "Justin I. Odegaard",
"authorSequenceNumber": 3,
"authorSlug": "justin-i-odegaard-zRGZz3",
"family": "Odegaard",
"given": "Justin I."
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "81078612",
"authorName": "Xiaojin Cui",
"authorSequenceNumber": 4,
"authorSlug": "xiaojin-cui-02DQmP",
"family": "Cui",
"given": "Xiaojin"
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "15221801",
"authorName": "Xiao Yu Tian",
"authorSequenceNumber": 5,
"authorSlug": "xiao-yu-tian-Pvz4rQ",
"family": "Tian",
"given": "Xiao Yu"
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "6048470",
"authorName": "Richard M. Locksley",
"authorSequenceNumber": 6,
"authorSlug": "richard-m-locksley-RVle83",
"family": "Locksley",
"given": "Richard M."
},
{
"affiliation": "University of Washington",
"affiliationID": "11969",
"affiliationSlug": "university-of-washington-5JeG",
"authorID": "398890",
"authorName": "Richard D. Palmiter",
"authorSequenceNumber": 7,
"authorSlug": "richard-d-palmiter-9g4O4",
"family": "Palmiter",
"given": "Richard D."
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "32477922",
"authorName": "Ajay Chawla",
"authorSequenceNumber": 8,
"authorSlug": "ajay-chawla-xpjLMg",
"family": "Chawla",
"given": "Ajay"
}
],
"doi": "10.1016/j.cell.2014.03.066",
"editorialNotices": [],
"id": 67158910,
"issns": [
"0092-8674"
],
"issue": "6",
"journal": "Cell",
"journalSlug": "pnm4z",
"keywords": [
"Article"
],
"memberId": 78,
"normalizedTypes": [
"article"
],
"page": "1292-1308",
"preprintLinks": [],
"publicationLinks": [],
"publisher": "Elsevier BV",
"retracted": false,
"shortJournal": "Cell",
"slug": "eosinophils-and-type-2-cytokine-64K4kr",
"title": "Eosinophils and Type 2 Cytokine Signaling in Macrophages Orchestrate Development of Functional Beige Fat",
"type": "journal-article",
"volume": "157",
"year": 2014
},
"10.1016/j.celrep.2016.06.007": {
"abstract": "Summary\nClostridium difficile infection (CDI) is the most common cause of hospital-acquired infection in the United States. Host susceptibility and the severity of infection are influenced by disruption of the microbiota and the immune response. However, how the microbiota regulates immune responses to mediate CDI outcome remains unclear. Here, we investigated the role of the microbiota-linked cytokine IL-25 during infection. Intestinal IL-25 was suppressed during CDI in humans and mice. Restoration of IL-25 reduced CDI-associated mortality and tissue pathology even though equivalent levels of C. difficile bacteria and toxin remained in the gut. IL-25 protection was mediated by gut eosinophils, as demonstrated by an increase in intestinal eosinophils and a loss of IL-25 protection upon eosinophil depletion. These findings support a mechanism whereby the induction of IL-25-mediated eosinophilia can reduce host mortality during active CDI. This work may provide targets for future development of microbial or immune-based therapies.",
"authors": [
{
"affiliation": "University of Virginia",
"affiliationID": "26257",
"affiliationSlug": "university-of-virginia-GAeJ",
"authorID": "9988090",
"authorName": "Erica L. Buonomo",
"authorSequenceNumber": 1,
"authorSlug": "erica-l-buonomo-9b1pNb",
"family": "Buonomo",
"given": "Erica L."
},
{
"affiliation": "University of Virginia",
"affiliationID": "26257",
"affiliationSlug": "university-of-virginia-GAeJ",
"authorID": "4017735",
"authorName": "Carrie A. Cowardin",
"authorSequenceNumber": 2,
"authorSlug": "carrie-a-cowardin-K6lp3p",
"family": "Cowardin",
"given": "Carrie A."
},
{
"affiliation": "University of Virginia",
"affiliationID": "26257",
"affiliationSlug": "university-of-virginia-GAeJ",
"authorID": "24766195",
"authorName": "Madeline G. Wilson",
"authorSequenceNumber": 3,
"authorSlug": "madeline-g-wilson-Yjv6QD",
"family": "Wilson",
"given": "Madeline G."
},
{
"affiliation": "University of Virginia",
"affiliationID": "26257",
"affiliationSlug": "university-of-virginia-GAeJ",
"authorID": "67903236",
"authorName": "Mahmoud M. Saleh",
"authorSequenceNumber": 4,
"authorSlug": "mahmoud-m-saleh-l166PE",
"family": "Saleh",
"given": "Mahmoud M."
},
{
"affiliation": "University of Virginia",
"affiliationID": "26257",
"affiliationSlug": "university-of-virginia-GAeJ",
"authorID": "6063859",
"authorName": "Patcharin Pramoonjago",
"authorSequenceNumber": 5,
"authorSlug": "patcharin-pramoonjago-b2rY3k",
"family": "Pramoonjago",
"given": "Patcharin"
},
{
"affiliation": "University of Virginia",
"affiliationID": "26257",
"affiliationSlug": "university-of-virginia-GAeJ",
"authorID": "21744467",
"authorName": "William A. Petri",
"authorSequenceNumber": 6,
"authorSlug": "william-a-petri-JlYGXE",
"family": "Petri",
"given": "William A."
}
],
"doi": "10.1016/j.celrep.2016.06.007",
"editorialNotices": [],
"id": 67169759,
"issns": [
"2211-1247"
],
"issue": "2",
"journal": "Cell Reports",
"journalSlug": "b2DYr",
"keywords": [
"Article"
],
"memberId": 78,
"normalizedTypes": [
"article"
],
"page": "432-443",
"preprintLinks": [],
"publicationLinks": [],
"publisher": "Elsevier BV",
"retracted": false,
"shortJournal": "Cell Reports",
"slug": "microbiota-regulated-il-25-increases-eosinophil-number-bmapM1",
"title": "Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection",
"type": "journal-article",
"volume": "16",
"year": 2016
},
"10.1016/j.molmet.2017.12.004": {
"abstract": "ObjectiveObesity is a metabolic disorder that has reached epidemic proportions worldwide and leads to increased risk for diabetes, cardiovascular disease, asthma, certain cancers, and various other diseases. Obesity and its comorbidities are associated with impaired adipose tissue (AT) function. In the last decade, eosinophils have been identified as regulators of proper AT function. Our study aimed to determine whether normalizing the number of AT eosinophils in obese mice, to those of lean healthy mice, would reduce obesity and/or improve metabolic fitness.MethodsC57BL/6J mice fed a high fat diet (HFD) were simultaneously given recombinant interleukin-5 (rIL5) for 8 weeks to increase AT eosinophils. Metabolic fitness was tested by evaluating weight gain, AT inflammation, glucose, lipid, and mixed-meal tolerance, AT insulin signaling, energy substrate utilization, energy expenditure, and white AT beiging capacity.ResultsEosinophils were increased ∼3-fold in AT of obese HFD-fed mice treated with rIL5, and thus were restored to levels observed in lean healthy mice. However, there were no significant differences in rIL5-treated mice among the above listed comprehensive set of metabolic assays, despite the increased AT eosinophils.ConclusionsWe have shown that restoring obese AT eosinophils to lean healthy levels is not sufficient to allow for improvement in any of a range of metabolic features otherwise impaired in obesity. Thus, the mechanisms that identified eosinophils as positive regulators of AT function, and therefore systemic health, are more complex than initially understood and will require further study to fully elucidate.",
"authors": [
{
"affiliation": "Vanderbilt University",
"affiliationID": "16364",
"affiliationSlug": "vanderbilt-university-ypnx",
"authorID": "11125700",
"authorName": "W. Reid Bolus",
"authorSequenceNumber": 1,
"authorSlug": "w-reid-bolus-38VwWO",
"family": "Bolus",
"given": "W. Reid"
},
{
"affiliation": "Vanderbilt University",
"affiliationID": "16364",
"affiliationSlug": "vanderbilt-university-ypnx",
"authorID": "56697354",
"authorName": "Kristin R. Peterson",
"authorSequenceNumber": 2,
"authorSlug": "kristin-r-peterson-6jwyP9",
"family": "Peterson",
"given": "Kristin R."
},
{
"affiliation": "Vanderbilt University",
"affiliationID": "16364",
"affiliationSlug": "vanderbilt-university-ypnx",
"authorID": "8524948",
"authorName": "Merla J. Hubler",
"authorSequenceNumber": 3,
"authorSlug": "merla-j-hubler-WGdxJO",
"family": "Hubler",
"given": "Merla J."
},
{
"affiliation": "Vanderbilt University",
"affiliationID": "16364",
"affiliationSlug": "vanderbilt-university-ypnx",
"authorID": "21870360",
"authorName": "Arion Kennedy",
"authorSequenceNumber": 4,
"authorSlug": "arion-kennedy-Qkw9NX",
"family": "Kennedy",
"given": "Arion"
},
{
"affiliation": "Vanderbilt University",
"affiliationID": "16364",
"affiliationSlug": "vanderbilt-university-ypnx",
"authorID": "67455575",
"authorName": "Marnie L. Gruen",
"authorSequenceNumber": 5,
"authorSlug": "marnie-l-gruen-ZkMNv9",
"family": "Gruen",
"given": "Marnie L."
},
{
"affiliation": "Vanderbilt University",
"affiliationID": "16364",
"affiliationSlug": "vanderbilt-university-ypnx",
"authorID": "3944334",
"authorName": "Alyssa H. Hasty",
"authorSequenceNumber": 6,
"authorSlug": "alyssa-h-hasty-OVjb2k",
"family": "Hasty",
"given": "Alyssa H."
}
],
"doi": "10.1016/j.molmet.2017.12.004",
"editorialNotices": [],
"id": 242253400,
"issns": [
"2212-8778"
],
"journal": "Molecular Metabolism",
"journalSlug": "lZrJ3",
"keywords": [
"Original Article"
],
"memberId": 78,
"normalizedTypes": [
"article"
],
"page": "86-95",
"preprintLinks": [],
"publicationLinks": [],
"publisher": "Elsevier BV",
"retracted": false,
"shortJournal": "Molecular Metabolism",
"slug": "elevating-adipose-eosinophils-in-obese-3ndxRPK",
"title": "Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments",
"type": "journal-article",
"volume": "8",
"year": 2018
},
"10.1038/ijo.2008.229": {
"abstract": "Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.",
"authors": [
{
"affiliation": "Pennington Biomedical Research Center",
"affiliationID": "16649",
"affiliationSlug": "pennington-biomedical-research-center-A5ra",
"authorID": "14162755",
"authorName": "Jianping Ye",
"authorSequenceNumber": 1,
"authorSlug": "jianping-ye-e6J2MO",
"family": "Ye",
"given": "Jianping"
}
],
"doi": "10.1038/ijo.2008.229",
"editorialNotices": [],
"id": 81259318,
"issns": [
"0307-0565",
"1476-5497"
],
"issue": "1",
"journal": "International Journal of Obesity",
"journalSlug": "QePv9",
"keywords": [
"adipose tissue",
"insulin resistance",
"hypoxia",
"inflammation",
"angiogenesis"
],
"memberId": 297,
"normalizedTypes": [
"article"
],
"page": "54-66",
"preprintLinks": [],
"publicationLinks": [],
"publisher": "Springer Science and Business Media LLC",
"retracted": false,
"shortJournal": "Int J Obes",
"slug": "emerging-role-of-adipose-tissue-dlEPxb",
"title": "Emerging role of adipose tissue hypoxia in obesity and insulin resistance",
"type": "journal-article",
"volume": "33",
"year": 2008
},
"10.1038/mi.2014.123": {
"abstract": "Eosinophils are multifunctional leukocytes that reside in the gastrointestinal (GI) lamina propria, where their basal function remains largely unexplored. In this study, by examining mice with a selective deficiency of systemic eosinophils (by lineage ablation) or GI eosinophils (eotaxin-1/2 double–deficient or CC chemokine receptor 3–deficient), we show that eosinophils support immunoglobulin A (IgA) class switching, maintain intestinal mucus secretions, affect intestinal microbial composition, and promote the development of Peyer’s patches. Eosinophil-deficient mice showed reduced expression of mediators of secretory IgA production, including intestinal interleukin 1β (IL-1β), inducible nitric oxide synthase, lymphotoxin (LT) α, and LT-β, and reduced levels of retinoic acid-related orphan receptor gamma t–positive (ROR-γt+) innate lymphoid cells (ILCs) while maintaining normal levels of APRIL (a proliferation-inducing ligand), BAFF (B cell–activating factor of the tumor necrosis factor family), and TGF-β (transforming growth factor β). GI eosinophils expressed a relatively high level of IL-1β, and IL-1β–deficient mice manifested the altered gene expression profiles observed in eosinophil-deficient mice and decreased levels of IgA+ cells and ROR-γt+ ILCs. On the basis of these collective data, we propose that eosinophils are required for homeostatic intestinal immune responses including IgA production and that their affect is mediated via IL-1β in the small intestine.",
"authors": [
{
"affiliation": "Cincinnati Children's Hospital Medical Center",
"affiliationID": "16374",
"affiliationSlug": "cincinnati-children-s-hospital-medical-center-pADQ",
"authorID": "139679076",
"authorName": "Yun-Jae Jung",
"authorSequenceNumber": 1,
"authorSlug": "yun-jae-jung-2PO1JE",
"family": "Jung",
"given": "Yun-Jae"
},
{
"affiliation": "Cincinnati Children's Hospital Medical Center",
"affiliationID": "16374",
"affiliationSlug": "cincinnati-children-s-hospital-medical-center-pADQ",
"authorID": "17384861",
"authorName": "Ting Wen",
"authorSequenceNumber": 2,
"authorSlug": "ting-wen-EOXp5P",
"family": "Wen",
"given": "Ting"
},
{
"affiliation": "University of Cincinnati",
"affiliationID": "19659",
"affiliationSlug": "university-of-cincinnati-bQ3Z",
"authorID": "411647800",
"authorName": "M K Mingler",
"authorSequenceNumber": 3,
"authorSlug": "m-k-mingler-38LOGQO",
"family": "Mingler",
"given": "M K"
},
{
"affiliation": "University of Cincinnati",
"affiliationID": "19659",
"affiliationSlug": "university-of-cincinnati-bQ3Z",
"authorID": "346531809",
"authorName": "J M Caldwell",
"authorSequenceNumber": 4,
"authorSlug": "j-m-caldwell-vydAJ14",
"family": "Caldwell",
"given": "J M"
},
{
"affiliation": "University of Cincinnati",
"affiliationID": "19659",
"affiliationSlug": "university-of-cincinnati-bQ3Z",
"authorID": "48788791",
"authorName": "Y H Wang",
"authorSequenceNumber": 5,
"authorSlug": "y-h-wang-1vR92W",
"family": "Wang",
"given": "Y H"
},
{
"affiliation": "University of Alabama at Birmingham",
"affiliationID": "26599",
"affiliationSlug": "university-of-alabama-at-birmingham-eNxm",
"authorID": "69032083",
"authorName": "David D. Chaplin",
"authorSequenceNumber": 6,
"authorSlug": "david-d-chaplin-a66kyx",
"family": "Chaplin",
"given": "David D."
},
{
"affiliation": "Gachon University",
"affiliationID": "9120",
"affiliationSlug": "gachon-university-yJdl",
"authorID": "176464118",
"authorName": "E H Lee",
"authorSequenceNumber": 7,
"authorSlug": "e-h-lee-dvKK5a9",
"family": "Lee",
"given": "E H"
},
{
"affiliation": "Pohang University of Science and Technology",
"affiliationID": "12801",
"affiliationSlug": "pohang-university-of-science-and-Pl3k",
"authorID": "27638113",
"authorName": "Myoung Ho Jang",
"authorSequenceNumber": 8,
"authorSlug": "myoung-ho-jang-G2ygMb",
"family": "Jang",
"given": "Myoung Ho"
},
{
"affiliation": "Ewha Womans University",
"affiliationID": "20765",
"affiliationSlug": "ewha-womans-university-8Wb3",
"authorID": "20013547",
"authorName": "So Youn Woo",
"authorSequenceNumber": 9,
"authorSlug": "so-youn-woo-15xObj",
"family": "Woo",
"given": "So Youn"
},
{
"affiliation": "Ewha Womans University",
"affiliationID": "20765",
"affiliationSlug": "ewha-womans-university-8Wb3",
"authorID": "7285494",
"authorName": "Ju Young Seoh",
"authorSequenceNumber": 10,
"authorSlug": "ju-young-seoh-zR4kwE",
"family": "Seoh",
"given": "Ju Young"
},
{
"affiliation": "Osaka University",
"affiliationID": "2722",
"affiliationSlug": "osaka-university-xX9D",
"authorID": "20136199",
"authorName": "Masayuki Miyasaka",
"authorSequenceNumber": 11,
"authorSlug": "masayuki-miyasaka-enkk90",
"family": "Miyasaka",
"given": "Masayuki"
},
{
"affiliation": "University of Cincinnati",
"affiliationID": "19659",
"affiliationSlug": "university-of-cincinnati-bQ3Z",
"authorID": "11358116",
"authorName": "Marc E. Rothenberg",
"authorSequenceNumber": 12,
"authorSlug": "marc-e-rothenberg-QmeOgJ",
"family": "Rothenberg",
"given": "Marc E."
}
],
"doi": "10.1038/mi.2014.123",
"editorialNotices": [],
"id": 81304296,
"issns": [
"1933-0219",
"1935-3456"
],
"issue": "4",
"journal": "Mucosal Immunology",
"journalSlug": "OV5EQ",
"keywords": [
"Article"
],
"memberId": 297,
"normalizedTypes": [
"article"
],
"page": "930-942",
"preprintLinks": [],
"publicationLinks": [],
"publisher": "Springer Science and Business Media LLC",
"retracted": false,
"shortJournal": "Mucosal Immunol",
"slug": "il-1-in-eosinophil-mediated-small-intestinal-Mv4WYd",
"title": "IL-1β in eosinophil-mediated small intestinal homeostasis and IgA production",
"type": "journal-article",
"volume": "8",
"year": 2015
},
"10.1038/nature05483": {
"abstract": "Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions.",
"authors": [
{
"authorID": "23569687",
"authorName": "Evan D. Rosen",
"authorSequenceNumber": 1,
"authorSlug": "evan-d-rosen-mALkWz",
"family": "Rosen",
"given": "Evan D."
},
{
"affiliation": "Harvard University",
"affiliationID": "14927",
"affiliationSlug": "harvard-university-NmzP",
"authorID": "376984",
"authorName": "Bruce M. Spiegelman",
"authorSequenceNumber": 2,
"authorSlug": "bruce-m-spiegelman-LAYWm",
"family": "Spiegelman",
"given": "Bruce M."
}
],
"doi": "10.1038/nature05483",
"editorialNotices": [],
"id": 81323364,
"issns": [
"0028-0836",
"1476-4687"
],
"issue": "7121",
"journal": "Nature",
"journalSlug": "wmGvz",
"keywords": [],
"memberId": 297,
"normalizedTypes": [
"article"
],
"page": "847-853",
"preprintLinks": [],
"publicationLinks": [],
"publisher": "Springer Science and Business Media LLC",
"retracted": false,
"shortJournal": "Nature",
"slug": "adipocytes-as-regulators-of-energy-ymzOyl",
"title": "Adipocytes as regulators of energy balance and glucose homeostasis",
"type": "journal-article",
"volume": "444",
"year": 2006
},
"10.1038/nbt.1621": {
"abstract": "High-throughput mRNA sequencing (RNA-Seq) holds the promise of simultaneous transcript discovery and abundance estimation1-3. We introduce an algorithm for transcript assembly coupled with a statistical model for RNA-Seq experiments that produces estimates of abundances. Our algorithms are implemented in an open source software program called Cufflinks. To test Cufflinks, we sequenced and analyzed more than 430 million paired 75bp RNA-Seq reads from a mouse myoblast cell line representing a differentiation time series. We detected 13,692 known transcripts and 3,724 previously unannotated ones, 62% of which are supported by independent expression data or by homologous genes in other species. Analysis of transcript expression over the time series revealed complete switches in the dominant transcription start site (TSS) or splice-isoform in 330 genes, along with more subtle shifts in a further 1,304 genes. These dynamics suggest substantial regulatory flexibility and complexity in this well-studied model of muscle development.",
"authors": [
{
"affiliation": "University of Maryland, College Park",
"affiliationID": "2613",
"affiliationSlug": "university-of-maryland-college-park-G3YK",
"authorID": "8885272",
"authorName": "Cole Trapnell",
"authorSequenceNumber": 1,
"authorSlug": "cole-trapnell-wb9XKL",
"family": "Trapnell",
"given": "Cole"
},
{
"affiliation": "California Institute of Technology",
"affiliationID": "9687",
"affiliationSlug": "california-institute-of-technology-mb8j",
"authorID": "81257310",
"authorName": "Brian A. Williams",
"authorSequenceNumber": 2,
"authorSlug": "brian-a-williams-623WzM",
"family": "Williams",
"given": "Brian A."
},
{
"affiliation": "University of Maryland, College Park",
"affiliationID": "2613",
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{
"affiliation": "California Institute of Technology",
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{
"affiliation": "California Institute of Technology",
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{
"affiliation": "Washington University in St. Louis",
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{
"affiliation": "University of California, Berkeley",
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"1087-0156",
"1546-1696"
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"year": 2010
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"abstract": "Pluripotent mesenchymal stem cells in bone marrow differentiate into adipocytes, osteoblasts and other cells. Balanced cytodifferentiation of stem cells is essential for the formation and maintenance of bone marrow; however, the mechanisms that control this balance remain largely unknown. Whereas cytokines such as interleukin-1 (IL-1) and tumour-necrosis factor-alpha (TNF-alpha) inhibit adipogenesis, the ligand-induced transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), is a key inducer of adipogenesis. Therefore, regulatory coupling between cytokine- and PPAR-gamma-mediated signals might occur during adipogenesis. Here we show that the ligand-induced transactivation function of PPAR-gamma is suppressed by IL-1 and TNF-alpha, and that this suppression is mediated through NF-kappaB activated by the TAK1/TAB1/NF-kappaB-inducing kinase (NIK) cascade, a downstream cascade associated with IL-1 and TNF-alpha signalling. Unlike suppression of the PPAR-gamma transactivation function by mitogen-activated protein kinase-induced growth factor signalling through phosphorylation of the A/B domain, NF-kappaB blocks PPAR-gamma binding to DNA by forming a complex with PPAR-gamma and its AF-1-specific co-activator PGC-2. Our results suggest that expression of IL-1 and TNF-alpha in bone marrow may alter the fate of pluripotent mesenchymal stem cells, directing cellular differentiation towards osteoblasts rather than adipocytes by suppressing PPAR-gamma function through NF-kappaB activated by the TAK1/TAB1/NIK cascade.",
"authors": [
{
"affiliation": "University of Tokyo",
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"affiliation": "University of Tokyo",
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{
"affiliation": "University of Tokyo",
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"affiliation": "University of Tokyo",
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{
"affiliation": "University of Tokyo",
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"affiliation": "National Institute for Basic Biology",
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{
"date": "2014-10-31",
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"noticeDoi": "10.1038/ncb3068",
"status": "Has correction"
},
{
"date": "2014-10-31",
"doi": "10.1038/ncb942",
"noticeDoi": "10.1038/ncb3068",
"status": "Retracted"
}
],
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"year": 2003
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"authors": [
{
"affiliation": "University of Tokyo",
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{
"affiliation": "University of Tokyo",
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"abstract": "Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity associated insulin resistance and glucose intolerance. Here we demonstrate a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to activation of pro-inflammatory macrophages and T cells, and production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, while transfer of DIO-IgG rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities to manage the disease.",
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{
"affiliation": "Stanford University",
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},
{
"affiliation": "University of Toronto",
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"authorID": "8957022",
"authorName": "Shawn Winer",
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{
"affiliation": "Stanford University",
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{
"affiliation": "Stanford University",
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"given": "Persis P."
},
{
"affiliation": "University of Toronto",
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"authorName": "Jason Yantha",
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{
"affiliation": "University of Toronto",
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{
"affiliation": "University of Toronto",
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"authorName": "Ping Wu",
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{
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{
"affiliation": "Duke University",
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{
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},
"10.1038/nri2921": {
"abstract": "The worldwide epidemic of obesity has brought cons iderable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.",
"authors": [
{
"affiliation": "Nagoya University",
"affiliationID": "8173",
"affiliationSlug": "nagoya-university-rLD3",
"authorID": "25408956",
"authorName": "Noriyuki Ouchi",
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{
"affiliation": "Boston University",
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"authorName": "Jennifer L. Parker",
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"family": "Parker",
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{
"affiliation": "Boston University",
"affiliationID": "7891",
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"authorID": "10069091",
"authorName": "Jesse J. Lugus",
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{
"affiliation": "Boston University",
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"authorName": "Kenneth Walsh",
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],
"doi": "10.1038/nri2921",
"editorialNotices": [],
"id": 81483874,
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"1474-1733",
"1474-1741"
],
"issue": "2",
"journal": "Nature Reviews Immunology",
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"shortJournal": "Nat Rev Immunol",
"slug": "adipokines-in-inflammation-and-metabolic-ppPW3w",
"title": "Adipokines in inflammation and metabolic disease",
"type": "journal-article",
"volume": "11",
"year": 2011
},
"10.1038/oby.2009.192": {
"abstract": "Inflammation and insulin resistance associated with visceral obesity are important risk factors for the development of type 2 diabetes, atherosclerosis, and the metabolic syndrome. The 12/15‐lipoxygenase (12/15‐LO) enzyme has been linked to inflammatory changes in blood vessels that precede the development of atherosclerosis. The expression and role of 12/15‐LO in adipocytes have not been evaluated. We found that 12/15‐LO mRNA was dramatically upregulated in white epididymal adipocytes of high‐fat fed mice. 12/15‐LO was poorly expressed in 3T3‐L1 fibroblasts and was upregulated during differentiation into adipocytes. Interestingly, the saturated fatty acid palmitate, a major component of high fat diets, augmented expression of 12/15‐LO in vitro. When 3T3‐L1 adipocytes were treated with the 12/15‐LO products, 12‐hydroxyeicosatetranoic acid (12(S)‐HETE) and 12‐hydroperoxyeicosatetraenoic acid (12(S)‐HPETE), expression of proinflammatory cytokine genes, including tumor necrosis factor‐α (TNF‐α), monocyte chemoattractant protein 1 (MCP‐1), interleukin 6 (IL‐6), and IL‐12p40, was upregulated whereas anti‐inflammatory adiponectin gene expression was downregulated. 12/15‐LO products also augmented c‐Jun N‐terminal kinase 1 (JNK‐1) phosphorylation, a known negative regulator of insulin signaling. Consistent with impaired insulin signaling, we found that insulin‐stimulated 3T3‐L1 adipocytes exhibited decreased IRS‐1(Tyr) phosphorylation, increased IRS‐1(Ser) phosphorylation, and impaired Akt phosphorylation when treated with 12/15‐LO product. Taken together, our data suggest that 12/15‐LO products create a proinflammatory state and impair insulin signaling in 3T3‐L1 adipocytes. Because 12/15‐LO expression is upregulated in visceral adipocytes by high‐fat feeding in vivo and also by addition of palmitic acid in vitro, we propose that 12/15‐LO plays a role in promoting inflammation and insulin resistance associated with obesity.",
"authors": [
{
"affiliation": "Eastern Virginia Medical School",
"affiliationID": "382",
"affiliationSlug": "eastern-virginia-medical-school-VLP",
"authorID": "63079324",
"authorName": "Swarup K. Chakrabarti",
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"family": "Chakrabarti",
"given": "Swarup K."
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{
"affiliation": "Eastern Virginia Medical School",
"affiliationID": "382",
"affiliationSlug": "eastern-virginia-medical-school-VLP",
"authorID": "12170150",
"authorName": "Banumathi K. Cole",
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{
"affiliation": "University of Virginia",
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"authorID": "54942341",
"authorName": "Yeshao Wen",
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{
"affiliation": "University of Virginia",
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"authorID": "19537263",
"authorName": "Susanna R. Keller",
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{
"affiliation": "Eastern Virginia Medical School",
"affiliationID": "382",
"affiliationSlug": "eastern-virginia-medical-school-VLP",
"authorID": "16259863",
"authorName": "Jerry L. Nadler",
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],
"doi": "10.1038/oby.2009.192",
"editorialNotices": [],
"id": 81510862,
"issns": [
"1930-7381"
],
"issue": "9",
"journal": "Obesity",
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"slug": "12-15-lipoxygenase-products-induce-inflammation-and-dl8jmy",
"title": "12/15-Lipoxygenase Products Induce Inflammation and Impair Insulin Signaling in 3T3-L1 Adipocytes",
"type": "journal-article",
"volume": "17",
"year": 2009
},
"10.1038/s41598-017-06397-4": {
"abstract": "Eosinophils and their associated cytokines IL-4 and IL-5 are emerging as central orchestrators of the immune-metabolic axis. Herein, we demonstrate that cross-talk between the Ig-superfamily receptor CD300f and IL-5 is a key checkpoint that modifies the ability of eosinophils to regulate metabolic outcomes. Generation of Il5\nTg\n/Cd300f\n−/− mice revealed marked and distinct increases in eosinophil levels and their production of IL-4 in the white and brown adipose tissues. Consequently, Il5\nTg\n/Cd300f\n−/− mice had increased alternatively activated macrophage accumulation in the adipose tissue. Cd300f\n−/− mice displayed age-related accumulation of eosinophils and macrophages in the adipose tissue and decreased adipose tissue weight, which was associated with decreased diet-induced weight gain and insulin resistance. Notably, Il5\nTg\n/CD300f\n−/− were protected from diet-induced weight gain and glucose intolerance. These findings highlight the cross-talk between IL-5 receptor and CD300f as a novel pathway regulating adipose tissue eosinophils and offer new entry points for therapeutic intervention for obesity and its complications.",
"authors": [
{
"affiliation": "Tel Aviv University",
"affiliationID": "12679",
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"authorID": "11006029",
"authorName": "Perri Rozenberg",
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{
"affiliation": "Tel Aviv University",
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"authorID": "28124321",
"authorName": "Hadar Reichman",
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{
"affiliation": "Tel Aviv University",
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"authorID": "131934550",
"authorName": "Israel Zab-Bar",
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"given": "Israel"
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{
"affiliation": "Tel Aviv University",
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"authorID": "5216739",
"authorName": "Michal Itan",
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{
"affiliation": "Tel Aviv University",
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"authorID": "14034264",
"authorName": "Metsada Pasmanik-Chor",
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{
"affiliation": "Cincinnati Children's Hospital Medical Center",
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"authorID": "297869",
"authorName": "Carine Bouffi",
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{
"affiliation": "Tel Aviv University",
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"authorID": "1662244",
"authorName": "Udi Qimron",
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"authorID": "7517075",
"authorName": "Ido Bachelet",
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{
"affiliation": "Cincinnati Children's Hospital Medical Center",
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"authorID": "7740496",
"authorName": "Patricia C. Fulkerson",
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"authorSlug": "patricia-c-fulkerson-M22g0m",
"family": "Fulkerson",
"given": "Patricia C."
},
{
"affiliation": "Cincinnati Children's Hospital Medical Center",
"affiliationID": "16374",
"affiliationSlug": "cincinnati-children-s-hospital-medical-center-pADQ",
"authorID": "11358116",
"authorName": "Marc E. Rothenberg",
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{
"affiliation": "Tel Aviv University",
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"authorID": "121132203",
"authorName": "Ariel Munitz",
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],
"doi": "10.1038/s41598-017-06397-4",
"editorialNotices": [],
"id": 233718020,
"issns": [
"2045-2322"
],
"issue": "1",
"journal": "Scientific Reports",
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"Article"
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"retracted": false,
"shortJournal": "Sci Rep",
"slug": "cd300f-il-5-cross-talk-inhibits-adipose-tissue-y8Q5z9p",
"title": "CD300f:IL-5 cross-talk inhibits adipose tissue eosinophil homing and subsequent IL-4 production",
"type": "journal-article",
"volume": "7",
"year": 2017
},
"10.1038/s41598-018-28371-4": {
"abstract": "Accumulating data have indicated a fundamental role of eosinophils in regulating adipose tissue homeostasis. Here, we performed whole-genome RNA sequencing of the small intestinal tract, which suggested the presence of impaired lipid metabolism in eosinophil-deficient ΔdblGATA mice. ΔdblGATA mice fed a high-fat diet (HFD) showed reduced body fat mass, impaired enlargement of adipocytes, decreased expression of adipogenic genes, and developed glucose intolerance. HFD induced accumulation of eosinophils in the perigonadal white adipose tissue. Concordantly, adipocyte-differentiated 3T3-L1 cells promoted the migration of eosinophils through the expression of CCL11 (eotaxin-1) and likely promoted their survival through the expression of interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor. HFD-fed ΔdblGATA mice showed increased infiltration of macrophages, CD4+ T-cells, and B-cells, increased expression of interferon-γ, and decreased expression of IL-4 and IL-13 in white adipose tissue. Interferon-γ treatment significantly decreased lipid deposition in adipocyte-differentiated 3T3-L1 cells, while IL-4 treatment promoted lipid accumulation. Notably, HFD-fed ΔdblGATA mice showed increased lipid storage in the liver as compared with wild-type mice. We propose that obesity promotes the infiltration of eosinophils into adipose tissue that subsequently contribute to the metabolic homeostasis by promoting adipocyte maturation.",
"authors": [
{
"affiliation": "Gachon University",
"affiliationID": "9120",
"affiliationSlug": "gachon-university-yJdl",
"authorID": "152962979",
"authorName": "Eun-Hui Lee",
"authorSequenceNumber": 1,
"authorSlug": "eun-hui-lee-KQMmMe",
"family": "Lee",
"given": "Eun-Hui"
},
{
"affiliation": "Tel Aviv University",
"affiliationID": "12679",
"affiliationSlug": "tel-aviv-university-KPbp",
"authorID": "5216739",
"authorName": "Michal Itan",
"authorSequenceNumber": 2,
"authorSlug": "michal-itan-aXkmEv",
"family": "Itan",
"given": "Michal"
},
{
"affiliation": "Gachon University",
"affiliationID": "9120",
"affiliationSlug": "gachon-university-yJdl",
"authorID": "152979076",
"authorName": "Jinsun Jang",
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"authorSlug": "jinsun-jang-2Zd5bY",
"family": "Jang",
"given": "Jinsun"
},
{
"affiliation": "Gachon University",
"affiliationID": "9120",
"affiliationSlug": "gachon-university-yJdl",
"authorID": "152933925",
"authorName": "Hyeon-Jung Gu",
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"authorSlug": "hyeon-jung-gu-5O8x8G",
"family": "Gu",
"given": "Hyeon-Jung"
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{
"affiliation": "Tel Aviv University",
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"authorID": "11006029",
"authorName": "Perri Rozenberg",
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"given": "Perri"
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{
"affiliation": "Cincinnati Children's Hospital Medical Center",
"affiliationID": "16374",
"affiliationSlug": "cincinnati-children-s-hospital-medical-center-pADQ",
"authorID": "4965324",
"authorName": "Melissa K. Mingler",
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"family": "Mingler",
"given": "Melissa K."
},
{
"affiliation": "Cincinnati Children's Hospital Medical Center",
"affiliationID": "16374",
"affiliationSlug": "cincinnati-children-s-hospital-medical-center-pADQ",
"authorID": "17384861",
"authorName": "Ting Wen",
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"authorSlug": "ting-wen-EOXp5P",
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"given": "Ting"
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{
"affiliation": "Gachon University",
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"authorID": "38694820",
"authorName": "Jiyoung Yoon",
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"authorSlug": "jiyoung-yoon-ywPwN6",
"family": "Yoon",
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},
{
"affiliation": "Gachon University",
"affiliationID": "9120",
"affiliationSlug": "gachon-university-yJdl",
"authorID": "52112172",
"authorName": "Shi-Young Park",
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"authorSlug": "shi-young-park-wXpAje",
"family": "Park",
"given": "Shi-Young"
},
{
"affiliation": "Gachon University",
"affiliationID": "9120",
"affiliationSlug": "gachon-university-yJdl",
"authorID": "12711292",
"authorName": "Joo Young Roh",
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},
{
"affiliation": "Gachon University",
"affiliationID": "9120",
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"authorID": "8946745",
"authorName": "Cheol Soo Choi",
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"family": "Choi",
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},
{
"affiliation": "Gachon University",
"affiliationID": "9120",
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"authorID": "152936204",
"authorName": "Woo-Jae Park",
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"authorSlug": "woo-jae-park-Wwy42O",
"family": "Park",
"given": "Woo-Jae"
},
{
"affiliation": "Tel Aviv University",
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"authorID": "121132203",
"authorName": "Ariel Munitz",
"authorSequenceNumber": 13,
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"family": "Munitz",
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},
{
"affiliation": "Gachon University",
"affiliationID": "9120",
"affiliationSlug": "gachon-university-yJdl",
"authorID": "139679076",
"authorName": "Yun-Jae Jung",
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"authorSlug": "yun-jae-jung-2PO1JE",
"family": "Jung",
"given": "Yun-Jae"
}
],
"doi": "10.1038/s41598-018-28371-4",
"editorialNotices": [],
"id": 223144610,
"issns": [
"2045-2322"
],
"issue": "1",
"journal": "Scientific Reports",
"journalSlug": "n6W5k",
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"Article"
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"publisher": "Springer Science and Business Media LLC",
"retracted": false,
"shortJournal": "Sci Rep",
"slug": "eosinophils-support-adipocyte-maturation-and-68jbdR1",
"title": "Eosinophils support adipocyte maturation and promote glucose tolerance in obesity",
"type": "journal-article",
"volume": "8",
"year": 2018
},
"10.1053/j.gastro.2013.04.010": {
"abstract": "BACKGROUND & AIMS\nAn increased number of macrophages in adipose tissue is associated with insulin resistance and metabolic dysfunction in obese people. However, little is known about other immune cells in adipose tissue from obese people, and whether they contribute to insulin resistance. We investigated the characteristics of T cells in adipose tissue from metabolically abnormal insulin-resistant obese (MAO) subjects, metabolically normal insulin-sensitive obese (MNO) subjects, and lean subjects. Insulin sensitivity was determined by using the hyperinsulinemic euglycemic clamp procedure.\n\n\nMETHODS\nWe assessed plasma cytokine concentrations and subcutaneous adipose tissue CD4+ T-cell populations in 9 lean, 12 MNO, and 13 MAO subjects. Skeletal muscle and liver samples were collected from 19 additional obese patients undergoing bariatric surgery to determine the presence of selected cytokine receptors.\n\n\nRESULTS\nAdipose tissue from MAO subjects had 3- to 10-fold increases in numbers of CD4+ T cells that produce interleukin (IL)-22 and IL-17 (a T-helper [Th] 17 and Th22 phenotype) compared with MNO and lean subjects. MAO subjects also had increased plasma concentrations of IL-22 and IL-6. Receptors for IL-17 and IL-22 were expressed in human liver and skeletal muscle samples. IL-17 and IL-22 inhibited uptake of glucose in skeletal muscle isolated from rats and reduced insulin sensitivity in cultured human hepatocytes.\n\n\nCONCLUSIONS\nAdipose tissue from MAO individuals contains increased numbers of Th17 and Th22 cells, which produce cytokines that cause metabolic dysfunction in liver and muscle in vitro. Additional studies are needed to determine whether these alterations in adipose tissue T cells contribute to the pathogenesis of insulin resistance in obese people.",
"authors": [
{
"affiliation": "Washington University in St. Louis",
"affiliationID": "19037",
"affiliationSlug": "washington-university-in-st-louis-jjaJ",
"authorID": "6328562",
"authorName": "Elisa Fabbrini",
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"authorSlug": "elisa-fabbrini-dvbLj1",
"family": "Fabbrini",
"given": "Elisa"
},
{
"affiliation": "Washington University in St. Louis",
"affiliationID": "19037",
"affiliationSlug": "washington-university-in-st-louis-jjaJ",
"authorID": "19860613",
"authorName": "Marina Cella",
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"authorSlug": "marina-cella-G6AaLL",
"family": "Cella",
"given": "Marina"
},
{
"affiliation": "Washington University in St. Louis",
"affiliationID": "19037",
"affiliationSlug": "washington-university-in-st-louis-jjaJ",
"authorID": "64542774",
"authorName": "Steve A. Mccartney",
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"family": "Mccartney",
"given": "Steve A."
},
{
"affiliation": "Washington University in St. Louis",
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"authorName": "Anja Fuchs",
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"family": "Fuchs",
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{
"affiliation": "Washington University in St. Louis",
"affiliationID": "19037",
"affiliationSlug": "washington-university-in-st-louis-jjaJ",
"authorID": "1846449",
"authorName": "Nada A. Abumrad",
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"authorSlug": "nada-a-abumrad-A2edE",
"family": "Abumrad",
"given": "Nada A."
},
{
"affiliation": "Washington University in St. Louis",
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"authorID": "10659883",
"authorName": "Terri A. Pietka",
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"family": "Pietka",
"given": "Terri A."
},
{
"affiliation": "Washington University in St. Louis",
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"authorID": "13723397",
"authorName": "Zhouji Chen",
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"family": "Chen",
"given": "Zhouji"
},
{
"affiliation": "Washington University in St. Louis",
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"authorID": "22224481",
"authorName": "Brian N. Finck",
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{
"affiliation": "Washington University in St. Louis",
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"authorName": "Dong Ho Han",
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{
"affiliation": "Washington University in St. Louis",
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"abstract": "Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and may be related to alterations in fat metabolism. Fatless mice have been created using dominant-negative protein (A-ZIP/F-1) targeted gene expression in the adipocyte and shown to develop diabetes. To understand the mechanism responsible for the insulin resistance in these mice, we conducted hyperinsulinemic-euglycemic clamps in awake fatless and wild type littermates before the development of diabetes and examined insulin action and signaling in muscle and liver. We found the fatless mice to be severely insulinresistant, which could be attributed to defects in insulin action in muscle and liver. Both of these abnormalities were associated with defects in insulin activation of insulin receptor substrate-1 and -2-associated phosphatidylinositol 3-kinase activity and a 2-fold increase in muscle and liver triglyceride content. We also show that upon transplantation of fat tissue into these mice, triglyceride content in muscle and liver returned to normal as does insulin signaling and action. In conclusion, these results suggest that the development of insulin resistance in type 2 diabetes may be due to alterations in the partitioning of fat between the adipocyte and muscle/liver leading to accumulation of triglyceride in the latter tissues with subsequent impairment of insulin signaling and action.",
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"abstract": "Recent reports demonstrate T-cell infiltration of adipose tissue in early obesity. We hypothesized that interferon (IFN) ␥, a major T-cell inflammatory cytokine, would attenuate human adipocyte functions and sought to establish signaling mechanisms. Differentiated human adipocytes were treated with IFN␥ ؎ pharmacological inhibitors prior to insulin stimulation.",
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"affiliation": "University of Pennsylvania",
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"abstract": "Hypoxia is a common feature of solid tumors, particularly in glioblastoma (GBM), and known to be a poor prognosis factor in GBM patients. The growth of GBM is also associated with a marked inflammation partially characterized by an accumulation of macrophage (MΦ) of the M2 phenotype. However, the transition between M1 MΦ (antitumoral) and M2 MΦ (protumoral) phenotypes is a dynamic process. We made the assumption that oxygen (O2) availability could be a major regulator of this transition and that the intratumoral O2 gradient is of importance. We evaluated, in vivo, the impact of hypoxia on MΦ tropism and polarization in two models of human GBM, well differentiated by their degree of hypoxia. MΦ migration in the tumor was more pronounced in the more hypoxic tumor of the two GBM models. In the more hypoxic of the models, we have shown that MΦ migrated at the tumor site only when hypoxia takes place. We also demonstrated that the acquisition of the M2 phenotype was clearly an evolving phenomenon with hypoxia as the major trigger for this transition. In support of these in vivo finding, M0 but also M1 MΦ cultured in moderate or severe hypoxia displayed a phenotype close to that of M2 MΦ whose phenotype was further reinforced by severe hypoxia. These results highlight the role of hypoxia in the aggressiveness of GBM, in part, by transforming MΦ such that a protumoral activity is expressed.",
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"issue": "1",
"journal": "OncoImmunology",
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"Original Research"
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"abstract": "Much of the work conducted on adult stem cells has focused on mesenchymal stem cells (MSCs) found within the bone marrow stroma. Adipose tissue, like bone marrow, is derived from the embryonic mesenchyme and contains a stroma that is easily isolated. Preliminary studies have recently identified a putative stem cell population within the adipose stromal compartment. This cell population, termed processed lipoaspirate (PLA) cells, can be isolated from human lipoaspirates and, like MSCs, differentiate toward the osteogenic, adipogenic, myogenic, and chondrogenic lineages. To confirm whether adipose tissue contains stem cells, the PLA population and multiple clonal isolates were analyzed using several molecular and biochemical approaches. PLA cells expressed multiple CD marker antigens similar to those observed on MSCs. Mesodermal lineage induction of PLA cells and clones resulted in the expression of multiple lineage-specific genes and proteins. Furthermore, biochemical analysis also confirmed lineage-specific activity. In addition to mesodermal capacity, PLA cells and clones differentiated into putative neurogenic cells, exhibiting a neuronal-like morphology and expressing several proteins consistent with the neuronal phenotype. Finally, PLA cells exhibited unique characteristics distinct from those seen in MSCs, including differences in CD marker profile and gene expression.",
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"1059-1524",
"1939-4586"
],
"issue": "12",
"journal": "Molecular Biology of the Cell",
"journalSlug": "3naW2",
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"page": "4279-4295",
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"publisher": "American Society for Cell Biology (ASCB)",
"retracted": false,
"shortJournal": "MBoC",
"slug": "human-adipose-tissue-is-a-zgLwX8",
"title": "Human Adipose Tissue Is a Source of Multipotent Stem Cells",
"type": "journal-article",
"volume": "13",
"year": 2002
},
"10.1093/bioinformatics/btp101": {
"abstract": "Summary: We have developed ClueGO, an easy to use Cytoscape plug-in that strongly improves biological interpretation of large lists of genes. ClueGO integrates Gene Ontology (GO) terms as well as KEGG/BioCarta pathways and creates a functionally organized GO/pathway term network. It can analyze one or compare two lists of genes and comprehensively visualizes functionally grouped terms. A one-click update option allows ClueGO to automatically download the most recent GO/KEGG release at any time. ClueGO provides an intuitive representation of the analysis results and can be optionally used in conjunction with the GOlorize plug-in.Availability: http://www.ici.upmc.fr/cluego/cluegoDownload.shtmlContact: jerome.galon@crc.jussieu.frSupplementary information: Supplementary data are available at Bioinformatics online.",
"authors": [
{
"affiliation": "Inserm",
"affiliationID": "6896",
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"authorID": "190599640",
"authorName": "Gabriela-Luana Bindea",
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"family": "Bindea",
"given": "Gabriela-Luana"
},
{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
"affiliationSlug": "sorbonne-university-g0bQ",
"authorID": "5929588",
"authorName": "Bernhard Mlecnik",
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"family": "Mlecnik",
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{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
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"authorID": "175923479",
"authorName": "Bernhard Mlecnik",
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"family": "Mlecnik",
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},
{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
"affiliationSlug": "sorbonne-university-g0bQ",
"authorID": "6807462",
"authorName": "Hubert Hackl",
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"family": "Hackl",
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},
{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
"affiliationSlug": "sorbonne-university-g0bQ",
"authorID": "5188329",
"authorName": "Pornpimol Charoentong",
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{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
"affiliationSlug": "sorbonne-university-g0bQ",
"authorID": "67195293",
"authorName": "Marie Tosolini",
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"family": "Tosolini",
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},
{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
"affiliationSlug": "sorbonne-university-g0bQ",
"authorID": "7006357",
"authorName": "Amos Kirilovsky",
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},
{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
"affiliationSlug": "sorbonne-university-g0bQ",
"authorID": "7234686",
"authorName": "Wolf H. Fridman",
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"family": "Fridman",
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},
{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
"affiliationSlug": "sorbonne-university-g0bQ",
"authorID": "191883796",
"authorName": "Franck Pagès",
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},
{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
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"authorID": "51866335",
"authorName": "Zlatko Trajanoski",
"authorSequenceNumber": 9,
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"family": "Trajanoski",
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},
{
"affiliation": "Sorbonne University",
"affiliationID": "21314",
"affiliationSlug": "sorbonne-university-g0bQ",
"authorID": "23365565",
"authorName": "Jérôme Galon",
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"authorSlug": "jerome-galon-8NWDRx",
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}
],
"doi": "10.1093/bioinformatics/btp101",
"editorialNotices": [],
"id": 90562888,
"issns": [
"1460-2059",
"1367-4803"
],
"issue": "8",
"journal": "Bioinformatics",
"journalSlug": "PQ0m2",
"keywords": [
"Applications Note"
],
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"page": "1091-1093",
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"publicationLinks": [],
"publisher": "Oxford University Press (OUP)",
"retracted": false,
"slug": "cluego-a-cytoscape-plug-in-to-3bzmjd",
"title": "ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks",
"type": "journal-article",
"volume": "25",
"year": 2009
},
"10.1093/bioinformatics/btp120": {
"abstract": "Motivation: A new protocol for sequencing the messenger RNA in a cell, known as RNA-Seq, generates millions of short sequence fragments in a single run. These fragments, or ‘reads’, can be used to measure levels of gene expression and to identify novel splice variants of genes. However, current software for aligning RNA-Seq data to a genome relies on known splice junctions and cannot identify novel ones. TopHat is an efficient read-mapping algorithm designed to align reads from an RNA-Seq experiment to a reference genome without relying on known splice sites.Results: We mapped the RNA-Seq reads from a recent mammalian RNA-Seq experiment and recovered more than 72% of the splice junctions reported by the annotation-based software from that study, along with nearly 20 000 previously unreported junctions. The TopHat pipeline is much faster than previous systems, mapping nearly 2.2 million reads per CPU hour, which is sufficient to process an entire RNA-Seq experiment in less than a day on a standard desktop computer. We describe several challenges unique to ab initio splice site discovery from RNA-Seq reads that will require further algorithm development.Availability: TopHat is free, open-source software available from http://tophat.cbcb.umd.eduContact: cole@cs.umd.eduSupplementary information: Supplementary data are available at Bioinformatics online.",
"authors": [
{
"affiliation": "University of Maryland, College Park",
"affiliationID": "2613",
"affiliationSlug": "university-of-maryland-college-park-G3YK",
"authorID": "8885272",
"authorName": "Cole Trapnell",
"authorSequenceNumber": 1,
"authorSlug": "cole-trapnell-wb9XKL",
"family": "Trapnell",
"given": "Cole"
},
{
"affiliation": "University of Maryland, College Park",
"affiliationID": "2613",
"affiliationSlug": "university-of-maryland-college-park-G3YK",
"authorID": "8878157",
"authorName": "Lior Pachter",
"authorSequenceNumber": 2,
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"family": "Pachter",
"given": "Lior"
},
{
"affiliation": "University of Maryland, College Park",
"affiliationID": "2613",
"affiliationSlug": "university-of-maryland-college-park-G3YK",
"authorID": "483606902",
"authorName": "Steven L. Salzberg",
"authorSequenceNumber": 3,
"authorSlug": "steven-l-salzberg-9bPOnP9",
"family": "Salzberg",
"given": "Steven L."
}
],
"doi": "10.1093/bioinformatics/btp120",
"editorialNotices": [],
"id": 90562907,
"issns": [
"1460-2059",
"1367-4803"
],
"issue": "9",
"journal": "Bioinformatics",
"journalSlug": "PQ0m2",
"keywords": [
"Original Papers"
],
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"page": "1105-1111",
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"publicationLinks": [],
"publisher": "Oxford University Press (OUP)",
"retracted": false,
"slug": "tophat-discovering-splice-junctions-with-Y5Kj23",
"title": "TopHat: discovering splice junctions with RNA-Seq",
"type": "journal-article",
"volume": "25",
"year": 2009
},
"10.1126/science.1201475": {
"abstract": "Eosinophils are associated with helminth immunity and allergy, often in conjunction with alternatively activated macrophages (AAMs). Adipose tissue AAMs are necessary to maintain glucose homeostasis and are induced by the cytokine interleukin-4 (IL-4). Here, we show that eosinophils are the major IL-4-expressing cells in white adipose tissues of mice, and, in their absence, AAMs are greatly attenuated. Eosinophils migrate into adipose by an integrin-dependent process and reconstitute AAMs through an IL-4/IL-13-dependent process. Mice on high-fat diet develop increased body fat, impaired glucose tolerance and insulin resistance in the absence of eosinophils, and helminth-induced adipose eosinophilia enhances glucose tolerance. Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs.",
"authors": [
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "14547459",
"authorName": "Davina Wu",
"authorSequenceNumber": 1,
"authorSlug": "davina-wu-b8KyY8",
"family": "Wu",
"given": "Davina"
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "6805954",
"authorName": "Ari B. Molofsky",
"authorSequenceNumber": 2,
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"family": "Molofsky",
"given": "Ari B."
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "11178770",
"authorName": "Hong-Erh Liang",
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"family": "Liang",
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},
{
"affiliation": "Stanford University",
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"authorID": "10317769",
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},
{
"affiliation": "Stanford University",
"affiliationID": "23761",
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"authorName": "Hani A. Jouihan",
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},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "8379223",
"authorName": "Jennifer K. Bando",
"authorSequenceNumber": 6,
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"family": "Bando",
"given": "Jennifer K."
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "32477922",
"authorName": "Ajay Chawla",
"authorSequenceNumber": 7,
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"family": "Chawla",
"given": "Ajay"
},
{
"affiliation": "University of California, San Francisco",
"affiliationID": "12272",
"affiliationSlug": "university-of-california-san-francisco-w1Ry",
"authorID": "6048470",
"authorName": "Richard M. Locksley",
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"family": "Locksley",
"given": "Richard M."
}
],
"doi": "10.1126/science.1201475",
"editorialNotices": [],
"id": 103081497,
"issns": [
"0036-8075",
"1095-9203"
],
"issue": "6026",
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"Article"
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"page": "243-247",
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"publisher": "American Association for the Advancement of Science (AAAS)",
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"shortJournal": "Science",
"slug": "eosinophils-sustain-adipose-alternatively-activated-vMKdvV",
"title": "Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose Homeostasis",
"type": "journal-article",
"volume": "332",
"year": 2011
},
"10.1146/annurev-immunol-031210-101322": {
"abstract": "The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.",
"authors": [
{
"affiliation": "Harvard University",
"affiliationID": "14927",
"affiliationSlug": "harvard-university-NmzP",
"authorID": "16265116",
"authorName": "Margaret F. Gregor",
"authorSequenceNumber": 1,
"authorSlug": "margaret-f-gregor-Q6O5K9",
"family": "Gregor",
"given": "Margaret F."
},
{
"affiliation": "Harvard University",
"affiliationID": "14927",
"affiliationSlug": "harvard-university-NmzP",
"authorID": "24580538",
"authorName": "Gökhan S. Hotamisligil",
"authorSequenceNumber": 2,
"authorSlug": "gokhan-s-hotamisligil-Vj555z",
"family": "Hotamisligil",
"given": "Gökhan S."
}
],
"doi": "10.1146/annurev-immunol-031210-101322",
"editorialNotices": [],
"id": 105718425,
"issns": [
"0732-0582",
"1545-3278"
],
"issue": "1",
"journal": "Annual Review of Immunology",
"journalSlug": "ejgZO",
"keywords": [
"adiposity",
"metaflammation",
"insulin resistance",
"inflammatory signaling",
"organelle stress",
"nutrient signals vi Contents"
],
"memberId": 22,
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"page": "415-445",
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"shortJournal": "Annu. Rev. Immunol.",
"slug": "inflammatory-mechanisms-in-obesity-55ZYk2",
"title": "Inflammatory Mechanisms in Obesity",
"type": "journal-article",
"volume": "29",
"year": 2011
},
"10.1146/annurev.med.53.082901.104057": {
"abstract": "I review evidence that leptin is a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues during periods of overnutrition. When adipocytes store excess calories as triacylglycerol (TG), leptin secretion rises so as to prevent accumulation of lipids in nonadipose tissues, which are not adapted for TG storage. Whenever leptin action is lacking, whether through leptin deficiency or leptin resistance, overnutrition causes disease of nonadipose tissues with generalized steatosis, lipotoxicity, and lipoapoptosis. Examples of such disorders of liporegulation include generalized lipodystrophies, mutations of leptin and leptin receptor genes, and diet-induced obesity. Lipotoxicity of pancreatic beta-cells, myocardium, and skeletal muscle leads, respectively, to type 2 diabetes, cardiomyopathy, and insulin resistance. In humans this constellation of abnormalities is referred to as the metabolic syndrome, a major health problem in the United States. When lipids overaccumulate in nonadipose tissues during overnutrition, fatty acids enter deleterious pathways such as ceramide production, which, through increased nitric oxide formation, causes apoptosis of lipid-laden cells, such as beta-cells and cardiomyocytes. Lipoapoptosis can be prevented by caloric restriction, by thiazolidinedione treatment, and by administration of nitric oxide blockers. There is now substantial evidence that complications of human obesity may reflect lipotoxicity similar to that described in rodents.",
"authors": [
{
"affiliation": "The University of Texas Southwestern Medical Center",
"affiliationID": "3092",
"affiliationSlug": "the-university-of-texas-southwestern-W8Yd",
"authorID": "982324166",
"authorName": "Roger H. Unger",
"authorSequenceNumber": 1,
"authorSlug": "roger-h-unger-xPJRMOw",
"family": "Unger",
"given": "Roger H."
}
],
"doi": "10.1146/annurev.med.53.082901.104057",
"editorialNotices": [],
"id": 105740370,
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"0066-4219",
"1545-326X"
],
"issue": "1",
"journal": "Annual Review of Medicine",
"journalSlug": "vJGbV",
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],
"page": "319-336",
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"publisher": "Annual Reviews",
"retracted": false,
"shortJournal": "Annu. Rev. Med.",
"slug": "lipotoxic-diseases-RX8EN3",
"title": "Lipotoxic Diseases",
"type": "journal-article",
"volume": "53",
"year": 2002
},
"10.1172/jci15001": {
"abstract": "Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy",
"authors": [
{
"affiliation": "Yale University",
"affiliationID": "8068",
"affiliationSlug": "yale-university-kyQE",
"authorID": "19514059",
"authorName": "Kitt Falk Petersen",
"authorSequenceNumber": 1,
"authorSlug": "kitt-falk-petersen-bM98wW",
"family": "Petersen",
"given": "Kitt Falk"
},
{
"authorID": "101157744",
"authorName": "Elif A. Oral",
"authorSequenceNumber": 2,
"authorSlug": "elif-a-oral-3wQkPJ",
"family": "Oral",
"given": "Elif A."
},
{
"affiliation": "Yale University",
"affiliationID": "8068",
"affiliationSlug": "yale-university-kyQE",
"authorID": "148536730",
"authorName": "Sylvie Dufour",
"authorSequenceNumber": 3,
"authorSlug": "sylvie-dufour-pJ9mK3",
"family": "Dufour",
"given": "Sylvie"
},
{
"affiliation": "Yale University",
"affiliationID": "8068",
"affiliationSlug": "yale-university-kyQE",
"authorID": "1529050",
"authorName": "Douglas E. Befroy",
"authorSequenceNumber": 4,
"authorSlug": "douglas-e-befroy-zW4yx",
"family": "Befroy",
"given": "Douglas E."
},
{
"affiliation": "Yale University",
"affiliationID": "8068",
"affiliationSlug": "yale-university-kyQE",
"authorID": "24586504",
"authorName": "Charlotte E. Ariyan",
"authorSequenceNumber": 5,
"authorSlug": "charlotte-e-ariyan-Wa5r1N",
"family": "Ariyan",
"given": "Charlotte E."
},
{
"affiliation": "Yale University",
"affiliationID": "8068",
"affiliationSlug": "yale-university-kyQE",
"authorID": "18585489",
"authorName": "Chunli Yu",
"authorSequenceNumber": 6,
"authorSlug": "chunli-yu-Pv5xk0",
"family": "Yu",
"given": "Chunli"
},
{
"affiliation": "Yale University",
"affiliationID": "8068",
"affiliationSlug": "yale-university-kyQE",
"authorID": "7080077",
"authorName": "Gary W. Cline",
"authorSequenceNumber": 7,
"authorSlug": "gary-w-cline-n68Dgk",
"family": "Cline",
"given": "Gary W."
},
{
"affiliation": "Amgen",
"affiliationID": "18955",
"affiliationSlug": "amgen-eAJO",
"authorID": "7128516",
"authorName": "Alex M. DePaoli",
"authorSequenceNumber": 8,
"authorSlug": "alex-m-depaoli-QeZ4m9",
"family": "DePaoli",
"given": "Alex M."
},
{
"affiliation": "National Institutes of Health",
"affiliationID": "26753",
"affiliationSlug": "national-institutes-of-health-vVaJ",
"authorID": "19599942",
"authorName": "Simeon I. Taylor",
"authorSequenceNumber": 9,
"authorSlug": "simeon-i-taylor-4x3Zj3",
"family": "Taylor",
"given": "Simeon I."
},
{
"affiliation": "National Institutes of Health",
"affiliationID": "26753",
"affiliationSlug": "national-institutes-of-health-vVaJ",
"authorID": "7701276",
"authorName": "Phillip Gorden",
"authorSequenceNumber": 10,
"authorSlug": "phillip-gorden-2WWaKL",
"family": "Gorden",
"given": "Phillip"
},
{
"affiliation": "Yale University",
"affiliationID": "8068",
"affiliationSlug": "yale-university-kyQE",
"authorID": "5886223",
"authorName": "Gerald I. Shulman",
"authorSequenceNumber": 11,
"authorSlug": "gerald-i-shulman-J1LvKY",
"family": "Shulman",
"given": "Gerald I."
}
],
"doi": "10.1172/jci15001",
"editorialNotices": [],
"id": 108000450,
"issns": [
"0021-9738"
],
"issue": "10",
"journal": "Journal of Clinical Investigation",
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"publisher": "American Society for Clinical Investigation",
"shortJournal": "J. Clin. Invest.",
"slug": "leptin-reverses-insulin-resistance-and-zmylXY",
"title": "Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy",
"type": "journal-article",
"volume": "109",
"year": 2002
},
"10.1172/jci19246": {
"authors": [
{
"affiliation": "Columbia University",
"affiliationID": "8275",
"affiliationSlug": "columbia-university-Z3Ly",
"authorID": "150108093",
"authorName": "Stuart P. Weisberg",
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"family": "Weisberg",
"given": "Stuart P."
},
{
"authorID": "106203356",
"authorName": "Daniel McCann",
"authorSequenceNumber": 2,
"authorSlug": "daniel-mccann-0yx39y",
"family": "McCann",
"given": "Daniel"
},
{
"authorID": "28017296",
"authorName": "Manisha Desai",
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"authorSlug": "manisha-desai-MyWNpp",
"family": "Desai",
"given": "Manisha"
},
{
"authorID": "12962727",
"authorName": "Michael Rosenbaum",
"authorSequenceNumber": 4,
"authorSlug": "michael-rosenbaum-NYAma9",
"family": "Rosenbaum",
"given": "Michael"
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{
"authorID": "1464126",
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],
"doi": "10.1172/jci19246",
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"publisher": "American Society for Clinical Investigation",
"shortJournal": "J. Clin. Invest.",
"slug": "obesity-is-associated-with-macrophage-Xm896A",
"title": "Obesity is associated with macrophage accumulation in adipose tissue",
"type": "journal-article",
"volume": "112",
"year": 2003
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"abstract": "Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and beta cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as positively affected serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin completely rescued the diabetic phenotype in ob/ob mice. They displayed increased expression of PPARgamma target genes and a reduction in macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to an interesting dichotomy of increased fat mass associated with improvement in insulin sensitivity. Based on these data, we propose that adiponectin acts as a peripheral \"starvation\" signal promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. These mice therefore represent what we believe is a novel model of morbid obesity associated with an improved metabolic profile.",
"authors": [
{
"affiliation": "Yeshiva University",
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"affiliation": "Yeshiva University",
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"affiliation": "University of Cincinnati",
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"title": "Obesity-associated improvements in metabolic profile through expansion of adipose tissue",
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"affiliation": "National Institutes of Health",
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"shortJournal": "J. Clin. Invest.",
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"abstract": "Increases in eosinophil numbers are associated with infection and allergic diseases, including asthma, but there is also evidence that eosinophils contribute to homeostatic immune processes. In mice, the normal lung contains resident eosinophils (rEos), but their function has not been characterized. Here, we have reported that steady-state pulmonary rEos are IL-5-independent parenchymal Siglec-FintCD62L+CD101lo cells with a ring-shaped nucleus. During house dust mite-induced airway allergy, rEos features remained unchanged, and rEos were accompanied by recruited inflammatory eosinophils (iEos), which were defined as IL-5-dependent peribronchial Siglec-FhiCD62L-CD101hi cells with a segmented nucleus. Gene expression analyses revealed a more regulatory profile for rEos than for iEos, and correspondingly, mice lacking lung rEos showed an increase in Th2 cell responses to inhaled allergens. Such elevation of Th2 responses was linked to the ability of rEos, but not iEos, to inhibit the maturation, and therefore the pro-Th2 function, of allergen-loaded DCs. Finally, we determined that the parenchymal rEos found in nonasthmatic human lungs (Siglec-8+CD62L+IL-3Rlo cells) were phenotypically distinct from the iEos isolated from the sputa of eosinophilic asthmatic patients (Siglec-8+CD62LloIL-3Rhi cells), suggesting that our findings in mice are relevant to humans. In conclusion, our data define lung rEos as a distinct eosinophil subset with key homeostatic functions",
"authors": [
{
"affiliation": "University of Liège",
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{
"affiliation": "University of Liège",
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{
"affiliation": "University of Liège",
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"doi": "10.1172/jci85664",
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"title": "Lung-resident eosinophils represent a distinct regulatory eosinophil subset",
"type": "journal-article",
"volume": "126",
"year": 2016
},
"10.1186/s12944-015-0123-1": {
"abstract": "Insulin resistance is a multi-faceted disruption of the communication between insulin and the interior of a target cell. The underlying cause of insulin resistance appears to be inflammation that can either be increased or decreased by the fatty acid composition of the diet. However, the molecular basis for insulin resistance can be quite different in various organs. This review deals with various types of inflammatory inputs mediated by fatty acids, which affect the extent of insulin resistance in various organs.",
"authors": [
{
"authorID": "12372440",
"authorName": "Barry Sears",
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],
"doi": "10.1186/s12944-015-0123-1",
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"id": 110076748,
"issns": [
"1476-511X"
],
"issue": "1",
"journal": "Lipids in Health and Disease",
"journalSlug": "Nlkme",
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"Review"
],
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"publisher": "Springer Science and Business Media LLC",
"retracted": false,
"shortJournal": "Lipids Health Dis",
"slug": "the-role-of-fatty-acids-WWJ0Od",
"title": "The role of fatty acids in insulin resistance",
"type": "journal-article",
"volume": "14",
"year": 2015
},
"10.1194/jlr.m008771": {
"abstract": "Storing excess energy for future use during starvation is critical for the survival of mammals. Much of this energy is stored in the form of triacylglycerol (TAG) within lipid droplets, which are present most abundantly in adipocytes and which, in turn, accumulate in depots such as subcutaneous and visceral adipose tissue in mice and humans. TAG in lipid droplets is mobilized during starvation by lipase-catalyzed hydrolysis (lipolysis) to release energy in the forms of glycerol and free fatty acids, providing fuel to other cell types such as muscle and liver. Previous work investigating formation of lipid droplets and regulation of lipolysis has elucidated the importance of lipid dropletassociated proteins for these processes ( 1, 2 ). Based on shared sequence homology, one set of lipid droplet proteins is grouped as the perilipin-adipophilin-tail interacting protein 47 (PAT/TIP47) family of proteins ( 3 ). PAT-related proteins are functionally conserved from mammals to lower organisms such as Drosophila and Dictyostelium spp ( 4 ). In Drosophila , two PAT domain proteins are encoded by the Lsdp1 and Lsd2 genes. Drosophila loss-of-function Lsd2 mutants are lean, whereas Lsd2 overexpression causes obesity ( 5 ). In mammals, PAT proteins can be divided into exchangeable TAG-associated PAT proteins (EPATs) or constitutively TAG-associated PAT proteins (CPATs). EPATs include the TIP47/perilipin-3 (PLIN3), S3-12/PLIN4, and Abstract The lipid droplet-associated fat specifi c protein 27 (FSP27) suppresses lipolysis and thereby enhances triglyceride accumulation in adipocytes. We and others have recently found FSP27 to be a remarkably short-lived protein (half-life, 15 min) due to its rapid ubiquitination and proteasomal degradation. Thus, we tested the hypothesis that lipolytic agents such as tumor necrosis factor-␣ (TNF-␣ ) and isoproterenol modulate FSP27 levels to regulate FFA release. Consistent with this concept, we showed that the lipolytic actions of TNF-␣ , interleukin-1  (IL-1  ), and IFN-␥ are accompanied by marked decreases in FSP27 expression and lipid droplet size in mouse adipocytes. Similar depletion of FSP27 using short interfering RNA (siRNA) mimicked the lipolysis-enhancing effect of TNF-␣ , while maintaining stable FSP27 levels using expression of hemagglutinin epitopetagged FSP27 blocked TNF-␣ -mediated lipolysis. In contrast, we show the robust lipolytic action of isoproterenol is paradoxically associated with increases in FSP27 levels and a delayed degradation rate corresponding to decreased ubiquitination. This catecholamine-mediated increase in FSP27 abundance, probably a feedback mechanism for restraining excessive lipolysis by catecholamines, is mimicked by forskolin or 8-bromo-cAMP treatment and is prevented by the protein kinase A (PKA) inhibitor KT5720 or by PKA depletion using siRNA. Taken together, these data identify the regulation of FSP27 as an important intermediate in the mechanism of lipolysis in adipocytes in response to TNF-␣ and isoproterenol. -Ranjit, S",
"authors": [
{
"affiliation": "University of Massachusetts Medical School",
"affiliationID": "260",
"affiliationSlug": "university-of-massachusetts-medical-school-Qkx",
"authorID": "14107537",
"authorName": "Srijana Ranjit",
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"family": "Ranjit",
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},
{
"affiliation": "University of Massachusetts Medical School",
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{
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{
"affiliation": "Kobe University",
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"authorName": "Yoshikazu Tamori",
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{
"affiliation": "University of Massachusetts Medical School",
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{
"affiliation": "Tufts University",
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"authorName": "Andrew S. Greenberg",
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},
{
"affiliation": "Boston University",
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"authorID": "73159816",
"authorName": "Vishwajeet Puri",
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{
"affiliation": "University of Massachusetts Medical School",
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"authorID": "8333398",
"authorName": "Michael P. Czech",
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}
],
"doi": "10.1194/jlr.m008771",
"editorialNotices": [],
"id": 110258347,
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"0022-2275"
],
"issue": "2",
"journal": "Journal of Lipid Research",
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"shortJournal": "Journal of Lipid Research",
"slug": "regulation-of-fat-specific-protein-1LNjy6",
"title": "Regulation of fat specific protein 27 by isoproterenol and TNF-α to control lipolysis in murine adipocytes",
"type": "journal-article",
"volume": "52",
"year": 2011
},
"10.1194/jlr.m800132-jlr200": {
"abstract": "Chronic inflammation of adipose tissue in obesity is by now an established phenomenon, but the initiating event(s) of the inflammatory cascade are still unknown. We hypothesized that neutrophil infiltration into adipose tissue may precede macrophage infiltration as in classical immune responses. Here we demonstrate that early (3 and 7 days) after initiating high-fat feeding of C57BL/6J mice, neutrophils transiently infiltrate the parenchyma of intra-abdominal adipose tissue. Mean periepdidymal fat myeloperoxidase expression (representing neutrophils) was significantly increased 3.5-fold (P , 0.01) and 2.9-fold (P , 0.03), at days 3 and 7 compared with day 0. Immunohystochemistry analysis demonstrated a physical binding between neutrophils and adipocytes, which was supported by in vitro adherence assay: mouse peritoneal neutrophils adhered to a monolayer of 3T3-L1 mouse adipocytes, in a manner dependent on their activation state, 41.9 6 3.7% or 29.5 6 2%, by PMA or the IL-8 analog CXCL1 (KC), respectively, compared with 24.8 6 1.5% in unstimulated neutrophils, respectively. The degree of surface exposure of CD11b (Mac-1) corresponded to the percentage of adhered neutrophils. The adherence was prevented by preincubating neutrophils or adipocytes with anti-CD11b or anti-ICAM-1 antibodies. Furthermore, immunoprecipitation of CD11b from lysates of a mixed neutrophil-adipocyte cell population resulted in coimmunoprecipitation of ICAM-1, indicating that the interaction is mediated by neutrophil CD11b and adipocyte ICAM-1.-Elgazar-Carmon, V., A. Rudich, N. Hadad, and R. Levy. Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding.",
"authors": [
{
"affiliation": "Ben-Gurion University of the Negev",
"affiliationID": "22717",
"affiliationSlug": "ben-gurion-university-of-the-negev-ENx1",
"authorID": "1070938",
"authorName": "Vered Elgazar-Carmon",
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"family": "Elgazar-Carmon",
"given": "Vered"
},
{
"affiliation": "Ben-Gurion University of the Negev",
"affiliationID": "22717",
"affiliationSlug": "ben-gurion-university-of-the-negev-ENx1",
"authorID": "5757299",
"authorName": "Assaf Rudich",
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"authorSlug": "assaf-rudich-ejmwOr",
"family": "Rudich",
"given": "Assaf"
},
{
"affiliation": "Ben-Gurion University of the Negev",
"affiliationID": "22717",
"affiliationSlug": "ben-gurion-university-of-the-negev-ENx1",
"authorID": "47105233",
"authorName": "Nurit Hadad",
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"family": "Hadad",
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},
{
"affiliation": "Ben-Gurion University of the Negev",
"affiliationID": "22717",
"affiliationSlug": "ben-gurion-university-of-the-negev-ENx1",
"authorID": "56245434",
"authorName": "Rachel Levy",
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"authorSlug": "rachel-levy-O2xWKO",
"family": "Levy",
"given": "Rachel"
}
],
"doi": "10.1194/jlr.m800132-jlr200",
"editorialNotices": [],
"id": 110260909,
"issns": [
"0022-2275"
],
"issue": "9",
"journal": "Journal of Lipid Research",
"journalSlug": "y8j1x",
"keywords": [
"Supplementary key words inflammation",
"obesity",
"adipocytes"
],
"memberId": 78,
"normalizedTypes": [
"article"
],
"page": "1894-1903",
"preprintLinks": [],
"publicationLinks": [],
"publisher": "Elsevier BV",
"retracted": false,
"shortJournal": "Journal of Lipid Research",
"slug": "neutrophils-transiently-infiltrate-intra-abdominal-fat-vOGP4W",
"title": "Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding",
"type": "journal-article",
"volume": "49",
"year": 2008
},
"10.1371/journal.pone.0134089": {
"abstract": "Immune reactivity plays an important role in obesity-associated metabolic disorders. We investigated immunometabolic phenotype of C57Bl/6 and BALB/c mice, prototypical Th1 and Th2-type strains, fed chow or high-fat diet (HFD) for 24 weeks. In comparison to C57Bl/6 mice, chow-fed BALB/c mice had higher body weight and weight gain, lower glycemia, more pronounced liver steatosis, but less inflammation and collagen deposition in liver. In response to HFD C57Bl/6 mice exhibited higher weight gain, higher glycemia, HbA1c and liver glycogen content, increased amount of visceral adipose tissue (VAT) and number of VAT associated CD3+CXCR3+ T cells, CD11c+ dendritic cells (DCs) and F4/80+ macrophages than BALB/c mice. More numerous CD3+ and CD8+ T lymphocytes, myeloid DCs, proinflammatory macrophages (F4/80+CD11b+CD11+ and F4/80+IL-1β+) and CD11b+Ly6Chigh monocytes and higher levels of proinflammatory IL-6, TNF-α and IFN-γ were present in liver in HFD-fed C57Bl/6 mice compared with diet-matched BALB/c mice. As opposed to C57Bl/6 mice, HFD induced marked liver steatosis and upregulated the hepatic LXRα and PPARγ genes in BALB/c mice. C57Bl/6 mice fed HFD developed liver fibrosis and increased hepatic procollagen and TGF-β mRNA expression, and IL-33, IL-13 and TGF-β levels in liver homogenates, while BALB/c mice fed HFD had scarce collagen deposition in liver. The obtained results suggest inherent immunometabolic differences in C57Bl/6 and BALB/c mice. Moreover, HFD Th1-type mice on high fat diet regimen are more susceptible to adiposity, liver inflammation and fibrosis, while Th2-type mice to liver steatosis, which is associated with differential immune cell composition in metabolic tissues. Strain-dependent differences in immunometabolic phenotype may be relevant for studies of obesity-associated metabolic diseases in humans.",
"authors": [
{
"affiliation": "University of Kragujevac",
"affiliationID": "22460",
"affiliationSlug": "university-of-kragujevac-QWPM",
"authorID": "11814723",
"authorName": "Nemanja Jovicic",
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"family": "Jovicic",
"given": "Nemanja"
},
{
"affiliation": "University of Kragujevac",
"affiliationID": "22460",
"affiliationSlug": "university-of-kragujevac-QWPM",
"authorID": "11217656",
"authorName": "Ilija Jeftic",
"authorSequenceNumber": 2,
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"family": "Jeftic",
"given": "Ilija"
},
{
"affiliation": "University of Kragujevac",
"affiliationID": "22460",
"affiliationSlug": "university-of-kragujevac-QWPM",
"authorID": "8132872",
"authorName": "Ivan Jovanovic",
"authorSequenceNumber": 3,
"authorSlug": "ivan-jovanovic-wb0zdL",
"family": "Jovanovic",
"given": "Ivan"
},
{
"affiliation": "University of Kragujevac",
"affiliationID": "22460",
"affiliationSlug": "university-of-kragujevac-QWPM",
"authorID": "81803378",
"authorName": "Ivan Jovanović",
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"authorSlug": "ivan-jovanovic-OeRb04",
"family": "Jovanović",
"given": "Ivan"
},
{
"affiliation": "University of Kragujevac",
"affiliationID": "22460",
"affiliationSlug": "university-of-kragujevac-QWPM",
"authorID": "7345090",
"authorName": "Gordana Radosavljevic",
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"family": "Radosavljevic",
"given": "Gordana"
},
{
"affiliation": "University of Kragujevac",
"affiliationID": "22460",
"affiliationSlug": "university-of-kragujevac-QWPM",
"authorID": "7855593",
"authorName": "Nebojsa Arsenijevic",
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"authorSlug": "nebojsa-arsenijevic-ANxZXZ",
"family": "Arsenijevic",
"given": "Nebojsa"
},
{
"affiliation": "University of Kragujevac",
"affiliationID": "22460",
"affiliationSlug": "university-of-kragujevac-QWPM",
"authorID": "6059854",
"authorName": "Miodrag L. Lukic",
"authorSequenceNumber": 6,
"authorSlug": "miodrag-l-lukic-685gnX",
"family": "Lukic",
"given": "Miodrag L."
},
{
"affiliation": "University of Kragujevac",
"affiliationID": "22460",
"affiliationSlug": "university-of-kragujevac-QWPM",
"authorID": "7904963",
"authorName": "Nada Pejnovic",
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"given": "Nada"
}
],
"doi": "10.1371/journal.pone.0134089",
"editorialNotices": [],
"id": 114840636,
"issns": [
"1932-6203"
],
"issue": "7",
"journal": "Plos One",
"journalSlug": "lZbEk",
"keywords": [
"Research Article"
],
"memberId": 340,
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"article"
],
"page": "e0134089",
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"publisher": "Public Library of Science (PLoS)",
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"shortJournal": "PLoS ONE",
"slug": "differential-immunometabolic-phenotype-in-th1-lJkWKb",
"title": "Differential Immunometabolic Phenotype in Th1 and Th2 Dominant Mouse Strains in Response to High-Fat Feeding",
"type": "journal-article",
"volume": "10",
"year": 2015
},
"10.1530/joe-16-0229": {
"abstract": "Group 2 innate lymphoid cells (ILC2s) in white adipose tissue (WAT) promotes WAT browning and assists in preventing the development of obesity. However, how ILC2 in adipose tissue is regulated remains largely unknown. Here, our present study shows that ILC2s are present in brown adipose tissue (BAT) as well as subcutaneous and epididymal WAT (sWAT and eWAT). The fractions of ILC2s, Natural Killer T (NKT) cells and eosinophils in sWAT, eWAT and BAT are significantly decreased by high fat diet (HFD) feeding and leptin deficiency-induced obesity. Consistent with this, the adipose expression and circulating levels of IL-33, a key inducing cytokine of ILC2 are significantly downregulated by obesity. Furthermore, administration of IL-33 markedly increases the fraction of ILC2 and eosinophil as well as expression of UCP1 and tyrosine hydroxylase (TH), a rate-limiting enzyme in catecholamine biosynthesis, in adipose tissue of HFD-fed mice. On the other hand, cold exposure induces the expression levels of IL-33 and UCP1 and the population of ILC2 and eosinophil in sWAT, and these promoting effects of cold stress are reversed by neutralization of IL-33 signaling in vivo. Moreover, the basal and cold-induced IL-33 and ILC2/eosinophil pathways are significantly suppressed by sympathetic denervation via local injection of 6-hydroxydopamine (6-OHDA) in sWAT. Taken together, our data suggests that the ILC2/eosinophil axis in adipose tissue is regulated by sympathetic nervous system and obesity in IL-33-dependent manner, and IL-33-driven ILC2/eosinophil axis are implicated in the development of obesity.",
"authors": [
{
"affiliation": "Hunan Normal University",
"affiliationID": "14267",
"affiliationSlug": "hunan-normal-university-Jn2G",
"authorID": "20857129",
"authorName": "Xiaofeng Ding",
"authorSequenceNumber": 1,
"authorSlug": "xiaofeng-ding-rQzwdO",
"family": "Ding",
"given": "Xiaofeng"
},
{
"affiliation": "Central South University",
"affiliationID": "26050",
"affiliationSlug": "central-south-university-zdvb",
"authorID": "84945490",
"authorName": "Yan Luo",
"authorSequenceNumber": 2,
"authorSlug": "yan-luo-9k1n5E",
"family": "Luo",
"given": "Yan"
},
{
"authorID": "103107960",
"authorName": "Xing Zhang",
"authorSequenceNumber": 3,
"authorSlug": "xing-zhang-Qlp0a9",
"family": "Zhang",
"given": "Xing"
},
{
"authorID": "61202478",
"authorName": "Handong Zheng",
"authorSequenceNumber": 4,
"authorSlug": "handong-zheng-OdOzp6",
"family": "Zheng",
"given": "Handong"
},
{
"authorID": "149529729",
"authorName": "Xin Yang",
"authorSequenceNumber": 5,
"authorSlug": "xin-yang-r55Xv4",
"family": "Yang",
"given": "Xin"
},
{
"authorID": "14741551",
"authorName": "Xuexian O. Yang",
"authorSequenceNumber": 6,
"authorSlug": "xuexian-o-yang-YDngGP",
"family": "Yang",
"given": "Xuexian O."
},
{
"affiliation": "Central South University",
"affiliationID": "26050",
"affiliationSlug": "central-south-university-zdvb",
"authorID": "14791762",
"authorName": "Meilian Liu",
"authorSequenceNumber": 7,
"authorSlug": "meilian-liu-dK4QJG",
"family": "Liu",
"given": "Meilian"
}
],
"doi": "10.1530/joe-16-0229",
"editorialNotices": [],
"id": 117609312,
"issns": [
"0022-0795",
"1479-6805"
],
"issue": "1",
"journal": "Journal of Endocrinology",
"journalSlug": "r6v4w",
"keywords": [
"Article"
],
"memberId": 416,
"normalizedTypes": [
"article"
],
"page": "35-48",
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"publicationLinks": [],
"publisher": "Bioscientifica",
"retracted": false,
"slug": "il-33-driven-ilc2-eosinophil-axis-in-fat-0Yeywr",
"title": "IL-33-driven ILC2/eosinophil axis in fat is induced by sympathetic tone and suppressed by obesity",
"type": "journal-article",
"volume": "231",
"year": 2016
}
},
"result": {
"citations": [
{
"refLocation": "b13/1",
"snippet": "Adipose tissue regulates energy homeostasis through the storage of excess calories and the secretion of adipocyte-derived secretory proteins such as leptin, adiponectin, and resistin 10,11 . However, excessive caloric Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 SCIentIfIC REPORTS | (2018) 8:9894 | intake induces the overexpansion of adipocytes, which results in inflammatory responses within adipose tissue 12 .Obesity-related metabolic dysfunctions are associated with an excessive infiltration of immune cells and chronic inflammation in adipose tissue <cite data-doi=\"10.1146/annurev-immunol-031210-101322\">13,</cite><cite data-doi=\"10.1038/nature05483\">14</cite> .Here, we used eosinophil-deficient ∆dblGATA and wild-type (WT) mice to investigate the roles of eosinophils in obesity, adipose tissue maturation, and associated metabolic responses. We performed whole-genome RNA sequencing of the small intestinal tract, which suggested the presence of a defective lipid metabolism in the absence of eosinophils.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1146/annurev-immunol-031210-101322"
},
{
"refLocation": "b14/1",
"snippet": "Adipose tissue regulates energy homeostasis through the storage of excess calories and the secretion of adipocyte-derived secretory proteins such as leptin, adiponectin, and resistin 10,11 . However, excessive caloric Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 SCIentIfIC REPORTS | (2018) 8:9894 | intake induces the overexpansion of adipocytes, which results in inflammatory responses within adipose tissue 12 .Obesity-related metabolic dysfunctions are associated with an excessive infiltration of immune cells and chronic inflammation in adipose tissue <cite data-doi=\"10.1146/annurev-immunol-031210-101322\">13,</cite><cite data-doi=\"10.1038/nature05483\">14</cite> .Here, we used eosinophil-deficient ∆dblGATA and wild-type (WT) mice to investigate the roles of eosinophils in obesity, adipose tissue maturation, and associated metabolic responses. We performed whole-genome RNA sequencing of the small intestinal tract, which suggested the presence of a defective lipid metabolism in the absence of eosinophils.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/nature05483"
},
{
"refLocation": "b13/2",
"snippet": "Obesity-related metabolic dysfunctions are associated with an excessive infiltration of immune cells and chronic inflammation in adipose tissue <cite data-doi=\"10.1146/annurev-immunol-031210-101322\">13,</cite><cite data-doi=\"10.1038/nature05483\">14</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1146/annurev-immunol-031210-101322"
},
{
"refLocation": "b14/2",
"snippet": "Obesity-related metabolic dysfunctions are associated with an excessive infiltration of immune cells and chronic inflammation in adipose tissue <cite data-doi=\"10.1146/annurev-immunol-031210-101322\">13,</cite><cite data-doi=\"10.1038/nature05483\">14</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/nature05483"
},
{
"refLocation": "b15/1",
"snippet": "S1). Of note, genes associated with lipid metabolism, such as Retnlg, Alox15, and Drd2 <cite data-doi=\"10.1038/oby.2009.192\">[15]</cite><cite data-doi=\"10.1006/bmmb.1993.1059\">[16]</cite><cite data-doi=\"10.1007/s00125-005-1735-1\">[17]</cite> were included in the top 10 downregulated genes (Table S1). Additionally, a GO analysis of the downregulated genes and visualization of a functionally grouped network using the ClueGO plugin <cite data-doi=\"10.1093/bioinformatics/btp101\">18</cite> suggested a defect in lipase activity (Table S3 and Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/oby.2009.192"
},
{
"refLocation": "b16/1",
"snippet": "S1). Of note, genes associated with lipid metabolism, such as Retnlg, Alox15, and Drd2 <cite data-doi=\"10.1038/oby.2009.192\">[15]</cite><cite data-doi=\"10.1006/bmmb.1993.1059\">[16]</cite><cite data-doi=\"10.1007/s00125-005-1735-1\">[17]</cite> were included in the top 10 downregulated genes (Table S1). Additionally, a GO analysis of the downregulated genes and visualization of a functionally grouped network using the ClueGO plugin <cite data-doi=\"10.1093/bioinformatics/btp101\">18</cite> suggested a defect in lipase activity (Table S3 and Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1006/bmmb.1993.1059"
},
{
"refLocation": "b17/1",
"snippet": "S1). Of note, genes associated with lipid metabolism, such as Retnlg, Alox15, and Drd2 <cite data-doi=\"10.1038/oby.2009.192\">[15]</cite><cite data-doi=\"10.1006/bmmb.1993.1059\">[16]</cite><cite data-doi=\"10.1007/s00125-005-1735-1\">[17]</cite> were included in the top 10 downregulated genes (Table S1). Additionally, a GO analysis of the downregulated genes and visualization of a functionally grouped network using the ClueGO plugin <cite data-doi=\"10.1093/bioinformatics/btp101\">18</cite> suggested a defect in lipase activity (Table S3 and Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1007/s00125-005-1735-1"
},
{
"refLocation": "b18/1",
"snippet": "Of note, genes associated with lipid metabolism, such as Retnlg, Alox15, and Drd2 <cite data-doi=\"10.1038/oby.2009.192\">[15]</cite><cite data-doi=\"10.1006/bmmb.1993.1059\">[16]</cite><cite data-doi=\"10.1007/s00125-005-1735-1\">[17]</cite> were included in the top 10 downregulated genes (Table S1). Additionally, a GO analysis of the downregulated genes and visualization of a functionally grouped network using the ClueGO plugin <cite data-doi=\"10.1093/bioinformatics/btp101\">18</cite> suggested a defect in lipase activity (Table S3 and Fig. S2) and a significant decrease in the expression of Lpl was observed ( Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1093/bioinformatics/btp101"
},
{
"refLocation": "b10/1",
"snippet": "Eosinophil-deficient mice gained less weight and perigonadal fat mass and displayed impaired glucose tolerance on a HFD. Excess caloric intake induces expansion of fat mass and accelerates development of insulin resistance <cite data-doi=\"10.1172/jci31021\">10</cite> . To further examine the role of eosinophils in adipose tissue expansion and energy homeostasis, we fed 8-10-week-old male WT and ΔdblGATA mice with a HFD for 12 weeks and monitored their body weights weekly.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1172/jci31021"
},
{
"refLocation": "b19/1",
"snippet": "Eosinophil-deficient mice showed an impaired maturation of perigonadal adipocytes on a HFD. The inability of adipose tissue to expand to accommodate excess calories causes systemic insulin resistance and hyperglycaemia <cite data-doi=\"10.1172/jci7901\">19</cite> . As we observed an impaired WAT development in HFD-fed ΔdblGATA mice, which showed glucose intolerance, we examined whether eosinophils are required for adipocyte maturation in diet-induced obesity.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1172/jci7901"
},
{
"refLocation": "b20/1",
"snippet": "Adipocytes support the migration and survival of eosinophils. Since eosinophils are resident cells in the adipose tissue <cite data-doi=\"10.1038/s41598-017-06397-4\">20</cite> and ΔdblGATA mice showed an impairment of adipocyte maturation, we questioned whether adipocytes support the migration or survival of eosinophils. Eosinophils migrate in a manner dependent on CCL11 and its receptor, CC chemokine receptor (CCR) 3 2,21 .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/s41598-017-06397-4"
},
{
"refLocation": "b22/1",
"snippet": "The perigonadal adipose tissue of eosinophil-deficient mice showed an increased inflammatory response. Excess calorie intake results in chronic inflammation in adipose tissue involving an infiltration of various immune cells <cite data-doi=\"10.1172/jci19246\">[22]</cite><cite data-doi=\"10.1053/j.gastro.2013.04.010\">[23]</cite><cite data-doi=\"10.1038/nm.1964\">[24]</cite><cite data-doi=\"10.1038/nm.2353\">[25]</cite><cite data-doi=\"10.1194/jlr.m800132-jlr200\">[26]</cite> . In obesity, the infiltrated immune cells promote the production of pro-inflammatory cytokines that inhibit adipogenesis and insulin signalling <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1038/ncb942\">28</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1172/jci19246"
},
{
"refLocation": "b23/1",
"snippet": "The perigonadal adipose tissue of eosinophil-deficient mice showed an increased inflammatory response. Excess calorie intake results in chronic inflammation in adipose tissue involving an infiltration of various immune cells <cite data-doi=\"10.1172/jci19246\">[22]</cite><cite data-doi=\"10.1053/j.gastro.2013.04.010\">[23]</cite><cite data-doi=\"10.1038/nm.1964\">[24]</cite><cite data-doi=\"10.1038/nm.2353\">[25]</cite><cite data-doi=\"10.1194/jlr.m800132-jlr200\">[26]</cite> . In obesity, the infiltrated immune cells promote the production of pro-inflammatory cytokines that inhibit adipogenesis and insulin signalling <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1038/ncb942\">28</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1053/j.gastro.2013.04.010"
},
{
"refLocation": "b24/1",
"snippet": "The perigonadal adipose tissue of eosinophil-deficient mice showed an increased inflammatory response. Excess calorie intake results in chronic inflammation in adipose tissue involving an infiltration of various immune cells <cite data-doi=\"10.1172/jci19246\">[22]</cite><cite data-doi=\"10.1053/j.gastro.2013.04.010\">[23]</cite><cite data-doi=\"10.1038/nm.1964\">[24]</cite><cite data-doi=\"10.1038/nm.2353\">[25]</cite><cite data-doi=\"10.1194/jlr.m800132-jlr200\">[26]</cite> . In obesity, the infiltrated immune cells promote the production of pro-inflammatory cytokines that inhibit adipogenesis and insulin signalling <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1038/ncb942\">28</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/nm.1964"
},
{
"refLocation": "b25/1",
"snippet": "The perigonadal adipose tissue of eosinophil-deficient mice showed an increased inflammatory response. Excess calorie intake results in chronic inflammation in adipose tissue involving an infiltration of various immune cells <cite data-doi=\"10.1172/jci19246\">[22]</cite><cite data-doi=\"10.1053/j.gastro.2013.04.010\">[23]</cite><cite data-doi=\"10.1038/nm.1964\">[24]</cite><cite data-doi=\"10.1038/nm.2353\">[25]</cite><cite data-doi=\"10.1194/jlr.m800132-jlr200\">[26]</cite> . In obesity, the infiltrated immune cells promote the production of pro-inflammatory cytokines that inhibit adipogenesis and insulin signalling <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1038/ncb942\">28</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/nm.2353"
},
{
"refLocation": "b26/1",
"snippet": "The perigonadal adipose tissue of eosinophil-deficient mice showed an increased inflammatory response. Excess calorie intake results in chronic inflammation in adipose tissue involving an infiltration of various immune cells <cite data-doi=\"10.1172/jci19246\">[22]</cite><cite data-doi=\"10.1053/j.gastro.2013.04.010\">[23]</cite><cite data-doi=\"10.1038/nm.1964\">[24]</cite><cite data-doi=\"10.1038/nm.2353\">[25]</cite><cite data-doi=\"10.1194/jlr.m800132-jlr200\">[26]</cite> . In obesity, the infiltrated immune cells promote the production of pro-inflammatory cytokines that inhibit adipogenesis and insulin signalling <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1038/ncb942\">28</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1194/jlr.m800132-jlr200"
},
{
"refLocation": "b27/1",
"snippet": "Excess calorie intake results in chronic inflammation in adipose tissue involving an infiltration of various immune cells <cite data-doi=\"10.1172/jci19246\">[22]</cite><cite data-doi=\"10.1053/j.gastro.2013.04.010\">[23]</cite><cite data-doi=\"10.1038/nm.1964\">[24]</cite><cite data-doi=\"10.1038/nm.2353\">[25]</cite><cite data-doi=\"10.1194/jlr.m800132-jlr200\">[26]</cite> . In obesity, the infiltrated immune cells promote the production of pro-inflammatory cytokines that inhibit adipogenesis and insulin signalling <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1038/ncb942\">28</cite> . The total numbers of cells isolated from the perigonadal WAT of HFD-fed ΔdblGATA and WT mice were not significantly different (p = 0.1263, data not shown).",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1074/jbc.m109.061655"
},
{
"refLocation": "b28/1",
"snippet": "Excess calorie intake results in chronic inflammation in adipose tissue involving an infiltration of various immune cells <cite data-doi=\"10.1172/jci19246\">[22]</cite><cite data-doi=\"10.1053/j.gastro.2013.04.010\">[23]</cite><cite data-doi=\"10.1038/nm.1964\">[24]</cite><cite data-doi=\"10.1038/nm.2353\">[25]</cite><cite data-doi=\"10.1194/jlr.m800132-jlr200\">[26]</cite> . In obesity, the infiltrated immune cells promote the production of pro-inflammatory cytokines that inhibit adipogenesis and insulin signalling <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1038/ncb942\">28</cite> . The total numbers of cells isolated from the perigonadal WAT of HFD-fed ΔdblGATA and WT mice were not significantly different (p = 0.1263, data not shown).",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/ncb942"
},
{
"refLocation": "b29/1",
"section": "The cytokine expression profile in the perigonadal adipose t...",
"snippet": "Eosinophil-deficient mice showed lipid accumulation in the liver. Excessive lipid accumulation in non-adipose tissues such as the liver, muscle, and pancreas is closely associated with insulin resistance <cite data-doi=\"10.1007/s11892-008-0032-z\">29</cite> . Given that lipids tend to be stored ectopically in the absence of functional adipocytes <cite data-doi=\"10.1146/annurev.med.53.082901.104057\">30</cite> , we hypothesized that eosinophil deficiency would influence the development of ectopic fat accumulation.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1007/s11892-008-0032-z"
},
{
"refLocation": "b30/1",
"section": "The cytokine expression profile in the perigonadal adipose t...",
"snippet": "Excessive lipid accumulation in non-adipose tissues such as the liver, muscle, and pancreas is closely associated with insulin resistance <cite data-doi=\"10.1007/s11892-008-0032-z\">29</cite> . Given that lipids tend to be stored ectopically in the absence of functional adipocytes <cite data-doi=\"10.1146/annurev.med.53.082901.104057\">30</cite> , we hypothesized that eosinophil deficiency would influence the development of ectopic fat accumulation. The livers of HFD-fed ΔdblGATA mice exhibited a paler colour and more prominent lipid deposits than those of WT mice (Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1146/annurev.med.53.082901.104057"
},
{
"refLocation": "b31/1",
"section": "Discussion",
"snippet": "Although eosinophils have been characterized as destructive effector cells that mediate tissue damage during helminth infections and allergic diseases, they are found in various tissues under resting conditions without having obvious pro-inflammatory activities <cite data-doi=\"10.1172/jci85664\">31,</cite><cite data-doi=\"10.1038/mi.2014.123\">32</cite> . Accumulating evidence has indicated that tissue-resident eosinophils regulate biological processes that are not restricted to Th2 immune responses.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1172/jci85664"
},
{
"refLocation": "b32/1",
"section": "Discussion",
"snippet": "Although eosinophils have been characterized as destructive effector cells that mediate tissue damage during helminth infections and allergic diseases, they are found in various tissues under resting conditions without having obvious pro-inflammatory activities <cite data-doi=\"10.1172/jci85664\">31,</cite><cite data-doi=\"10.1038/mi.2014.123\">32</cite> . Accumulating evidence has indicated that tissue-resident eosinophils regulate biological processes that are not restricted to Th2 immune responses.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/mi.2014.123"
},
{
"refLocation": "b33/1",
"section": "Discussion",
"snippet": "Accumulating evidence has indicated that tissue-resident eosinophils regulate biological processes that are not restricted to Th2 immune responses. Eosinophils in adipose tissue promote the accumulation of alternatively activated macrophages, which protect against insulin resistance induced by obesity-associated changes such as the activation of innate immune activity, alterations in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition <cite data-doi=\"10.1016/j.cell.2012.02.017\">33</cite> . Obesity itself does not necessarily induce insulin resistance and primarily results from adipocytes expanding to buffer against excess nutrient uptake 9 .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1016/j.cell.2012.02.017"
},
{
"refLocation": "b4/1",
"section": "Discussion",
"snippet": "These cytokines provide signals that promote the permissive proliferation and differentiation of eosinophils 2,3 . These findings contrast with previous observations that suggested an inverse correlation between the abundance of eosinophils in adipose tissue and adiposity <cite data-doi=\"10.1126/science.1201475\">5,</cite><cite data-doi=\"10.1016/j.molmet.2017.12.004\">34,</cite><cite data-doi=\"10.1530/joe-16-0229\">35</cite> . The reasons for this difference are unclear, but mouse strains vary in their immunometabolic phenotypes <cite data-doi=\"10.1007/s00125-013-2846-8\">36</cite> , as evidenced by the difference between BALB/c and C57BL/6 mice in their immune cell profiles with a HFD <cite data-doi=\"10.1371/journal.pone.0134089\">37</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1126/science.1201475"
},
{
"refLocation": "b34/1",
"section": "Discussion",
"snippet": "These cytokines provide signals that promote the permissive proliferation and differentiation of eosinophils 2,3 . These findings contrast with previous observations that suggested an inverse correlation between the abundance of eosinophils in adipose tissue and adiposity <cite data-doi=\"10.1126/science.1201475\">5,</cite><cite data-doi=\"10.1016/j.molmet.2017.12.004\">34,</cite><cite data-doi=\"10.1530/joe-16-0229\">35</cite> . The reasons for this difference are unclear, but mouse strains vary in their immunometabolic phenotypes <cite data-doi=\"10.1007/s00125-013-2846-8\">36</cite> , as evidenced by the difference between BALB/c and C57BL/6 mice in their immune cell profiles with a HFD <cite data-doi=\"10.1371/journal.pone.0134089\">37</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1016/j.molmet.2017.12.004"
},
{
"refLocation": "b35/1",
"section": "Discussion",
"snippet": "These cytokines provide signals that promote the permissive proliferation and differentiation of eosinophils 2,3 . These findings contrast with previous observations that suggested an inverse correlation between the abundance of eosinophils in adipose tissue and adiposity <cite data-doi=\"10.1126/science.1201475\">5,</cite><cite data-doi=\"10.1016/j.molmet.2017.12.004\">34,</cite><cite data-doi=\"10.1530/joe-16-0229\">35</cite> . The reasons for this difference are unclear, but mouse strains vary in their immunometabolic phenotypes <cite data-doi=\"10.1007/s00125-013-2846-8\">36</cite> , as evidenced by the difference between BALB/c and C57BL/6 mice in their immune cell profiles with a HFD <cite data-doi=\"10.1371/journal.pone.0134089\">37</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1530/joe-16-0229"
},
{
"refLocation": "b36/1",
"section": "Discussion",
"snippet": "These findings contrast with previous observations that suggested an inverse correlation between the abundance of eosinophils in adipose tissue and adiposity <cite data-doi=\"10.1126/science.1201475\">5,</cite><cite data-doi=\"10.1016/j.molmet.2017.12.004\">34,</cite><cite data-doi=\"10.1530/joe-16-0229\">35</cite> . The reasons for this difference are unclear, but mouse strains vary in their immunometabolic phenotypes <cite data-doi=\"10.1007/s00125-013-2846-8\">36</cite> , as evidenced by the difference between BALB/c and C57BL/6 mice in their immune cell profiles with a HFD <cite data-doi=\"10.1371/journal.pone.0134089\">37</cite> . In line with this, chow diet-fed male C57BL/6 mice showed significantly more eosinophils in the perigonadal adipose tissue than BALB/c mice, while showing fewer eosinophils in the small intestine ( Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1007/s00125-013-2846-8"
},
{
"refLocation": "b37/1",
"section": "Discussion",
"snippet": "These findings contrast with previous observations that suggested an inverse correlation between the abundance of eosinophils in adipose tissue and adiposity <cite data-doi=\"10.1126/science.1201475\">5,</cite><cite data-doi=\"10.1016/j.molmet.2017.12.004\">34,</cite><cite data-doi=\"10.1530/joe-16-0229\">35</cite> . The reasons for this difference are unclear, but mouse strains vary in their immunometabolic phenotypes <cite data-doi=\"10.1007/s00125-013-2846-8\">36</cite> , as evidenced by the difference between BALB/c and C57BL/6 mice in their immune cell profiles with a HFD <cite data-doi=\"10.1371/journal.pone.0134089\">37</cite> . In line with this, chow diet-fed male C57BL/6 mice showed significantly more eosinophils in the perigonadal adipose tissue than BALB/c mice, while showing fewer eosinophils in the small intestine ( Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1371/journal.pone.0134089"
},
{
"refLocation": "b38/1",
"section": "Discussion",
"snippet": "S13). There are likely differences in microbiota, and thus endotoxin exposure may explain the weight difference between results of previous reports and those of our study, as exposure to microbial endotoxins may alter eosinophil maturation and activities <cite data-doi=\"10.1016/j.celrep.2016.06.007\">38</cite> . Considering that our results are consistent with previous reports indicating eosinophils role in the regulation of metabolic homeostasis <cite data-doi=\"10.1016/j.cell.2014.03.066\">4,</cite><cite data-doi=\"10.1126/science.1201475\">5,</cite><cite data-doi=\"10.1530/joe-16-0229\">35</cite> , we propose that differences in mice strain and cohort might account for the divergence on eosinophil abundance in the adipose tissue between this study and previous observations.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1016/j.celrep.2016.06.007"
},
{
"refLocation": "b3/1",
"section": "Discussion",
"snippet": "There are likely differences in microbiota, and thus endotoxin exposure may explain the weight difference between results of previous reports and those of our study, as exposure to microbial endotoxins may alter eosinophil maturation and activities <cite data-doi=\"10.1016/j.celrep.2016.06.007\">38</cite> . Considering that our results are consistent with previous reports indicating eosinophils role in the regulation of metabolic homeostasis <cite data-doi=\"10.1016/j.cell.2014.03.066\">4,</cite><cite data-doi=\"10.1126/science.1201475\">5,</cite><cite data-doi=\"10.1530/joe-16-0229\">35</cite> , we propose that differences in mice strain and cohort might account for the divergence on eosinophil abundance in the adipose tissue between this study and previous observations.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1016/j.cell.2014.03.066"
},
{
"refLocation": "b4/2",
"section": "Discussion",
"snippet": "There are likely differences in microbiota, and thus endotoxin exposure may explain the weight difference between results of previous reports and those of our study, as exposure to microbial endotoxins may alter eosinophil maturation and activities <cite data-doi=\"10.1016/j.celrep.2016.06.007\">38</cite> . Considering that our results are consistent with previous reports indicating eosinophils role in the regulation of metabolic homeostasis <cite data-doi=\"10.1016/j.cell.2014.03.066\">4,</cite><cite data-doi=\"10.1126/science.1201475\">5,</cite><cite data-doi=\"10.1530/joe-16-0229\">35</cite> , we propose that differences in mice strain and cohort might account for the divergence on eosinophil abundance in the adipose tissue between this study and previous observations.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1126/science.1201475"
},
{
"refLocation": "b35/2",
"section": "Discussion",
"snippet": "There are likely differences in microbiota, and thus endotoxin exposure may explain the weight difference between results of previous reports and those of our study, as exposure to microbial endotoxins may alter eosinophil maturation and activities <cite data-doi=\"10.1016/j.celrep.2016.06.007\">38</cite> . Considering that our results are consistent with previous reports indicating eosinophils role in the regulation of metabolic homeostasis <cite data-doi=\"10.1016/j.cell.2014.03.066\">4,</cite><cite data-doi=\"10.1126/science.1201475\">5,</cite><cite data-doi=\"10.1530/joe-16-0229\">35</cite> , we propose that differences in mice strain and cohort might account for the divergence on eosinophil abundance in the adipose tissue between this study and previous observations.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1530/joe-16-0229"
},
{
"refLocation": "b8/1",
"section": "Discussion",
"snippet": "The fat cells of adipose tissue are the only cells in the body that are designed to safely contain large amounts of fat <cite data-doi=\"10.1186/s12944-015-0123-1\">9</cite> . Therefore, the impaired development of perigonadal adipose tissue observed in HFD-fed ΔdblGATA mice may lead to the accumulation of lipid outside adipose tissue.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1186/s12944-015-0123-1"
},
{
"refLocation": "b33/2",
"section": "Discussion",
"snippet": "Therefore, the impaired development of perigonadal adipose tissue observed in HFD-fed ΔdblGATA mice may lead to the accumulation of lipid outside adipose tissue. The excessive accumulation of lipids in non-adipose tissues is closely associated with insulin resistance <cite data-doi=\"10.1016/j.cell.2012.02.017\">33</cite> , and we propose that ectopic fat accumulation in HFD-fed ΔdblGATA mice might account for their glucose intolerance. Although increased visceral adiposity has been implicated in hepatic insulin resistance, patients with severe lipodystrophy, as well as a mouse model of lipoatrophy, manifest insulin resistance associated with lipid deposition in the liver <cite data-doi=\"10.1172/jci15001\">39,</cite><cite data-doi=\"10.1074/jbc.275.12.8456\">40</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1016/j.cell.2012.02.017"
},
{
"refLocation": "b39/1",
"section": "Discussion",
"snippet": "The excessive accumulation of lipids in non-adipose tissues is closely associated with insulin resistance <cite data-doi=\"10.1016/j.cell.2012.02.017\">33</cite> , and we propose that ectopic fat accumulation in HFD-fed ΔdblGATA mice might account for their glucose intolerance. Although increased visceral adiposity has been implicated in hepatic insulin resistance, patients with severe lipodystrophy, as well as a mouse model of lipoatrophy, manifest insulin resistance associated with lipid deposition in the liver <cite data-doi=\"10.1172/jci15001\">39,</cite><cite data-doi=\"10.1074/jbc.275.12.8456\">40</cite> . The significant decrease in the expression of Pparg, which encodes a transcription factor involved in adipocyte differentiation, and genes associated with lipid droplet formation (Cav1, Cav2, Cd36, and Cidec) in the perigonadal WAT of HFD-fed ΔdblGATA mice ( Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1172/jci15001"
},
{
"refLocation": "b40/1",
"section": "Discussion",
"snippet": "The excessive accumulation of lipids in non-adipose tissues is closely associated with insulin resistance <cite data-doi=\"10.1016/j.cell.2012.02.017\">33</cite> , and we propose that ectopic fat accumulation in HFD-fed ΔdblGATA mice might account for their glucose intolerance. Although increased visceral adiposity has been implicated in hepatic insulin resistance, patients with severe lipodystrophy, as well as a mouse model of lipoatrophy, manifest insulin resistance associated with lipid deposition in the liver <cite data-doi=\"10.1172/jci15001\">39,</cite><cite data-doi=\"10.1074/jbc.275.12.8456\">40</cite> . The significant decrease in the expression of Pparg, which encodes a transcription factor involved in adipocyte differentiation, and genes associated with lipid droplet formation (Cav1, Cav2, Cd36, and Cidec) in the perigonadal WAT of HFD-fed ΔdblGATA mice ( Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1074/jbc.275.12.8456"
},
{
"refLocation": "b41/1",
"section": "Discussion",
"snippet": "3) suggests insufficient lipid storage in adipose tissue in the absence of eosinophils. Concordantly, the expression of Lpl, Slc2a4, and Adipoq, which are regulated by Pparg and involved in glucose homeostasis <cite data-doi=\"10.1074/jbc.m114.628487\">41</cite> , significantly decreased in the perigonadal adipose tissue of HFD-fed ΔdblGATA mice (Fig. 3).",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1074/jbc.m114.628487"
},
{
"refLocation": "b28/2",
"section": "Discussion",
"snippet": "We suggest that an altered immune environment in the perigonadal fat of HFD-fed ΔdblGATA accounts for the decreased expression of adipogenic genes. The exposure of preadipocytes to pro-inflammatory cytokines inhibits adipogenesis by reducing the expression of Pparg and inhibiting the adipogenic action of insulin <cite data-doi=\"10.1038/ncb942\">28</cite> . Th1 cytokines, including IFN-γ, can inhibit insulin signalling and lipid droplet formation <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1194/jlr.m008771\">42</cite> , while Th2 cytokines, including IL-4 and IL-13, can suppress inflammatory responses in adipose tissue <cite data-doi=\"10.1038/nri2921\">43</cite> .",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/ncb942"
},
{
"refLocation": "b27/2",
"section": "Discussion",
"snippet": "The exposure of preadipocytes to pro-inflammatory cytokines inhibits adipogenesis by reducing the expression of Pparg and inhibiting the adipogenic action of insulin <cite data-doi=\"10.1038/ncb942\">28</cite> . Th1 cytokines, including IFN-γ, can inhibit insulin signalling and lipid droplet formation <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1194/jlr.m008771\">42</cite> , while Th2 cytokines, including IL-4 and IL-13, can suppress inflammatory responses in adipose tissue <cite data-doi=\"10.1038/nri2921\">43</cite> . The increased expression of Ifng and decreased expression of Il4 and Il13 in the perigonadal fat of HFD-fed ΔdblGATA mice imply that the microenvironments of the WAT of these mice are unfavourable for adipocyte maturation.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1074/jbc.m109.061655"
},
{
"refLocation": "b42/1",
"section": "Discussion",
"snippet": "The exposure of preadipocytes to pro-inflammatory cytokines inhibits adipogenesis by reducing the expression of Pparg and inhibiting the adipogenic action of insulin <cite data-doi=\"10.1038/ncb942\">28</cite> . Th1 cytokines, including IFN-γ, can inhibit insulin signalling and lipid droplet formation <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1194/jlr.m008771\">42</cite> , while Th2 cytokines, including IL-4 and IL-13, can suppress inflammatory responses in adipose tissue <cite data-doi=\"10.1038/nri2921\">43</cite> . The increased expression of Ifng and decreased expression of Il4 and Il13 in the perigonadal fat of HFD-fed ΔdblGATA mice imply that the microenvironments of the WAT of these mice are unfavourable for adipocyte maturation.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1194/jlr.m008771"
},
{
"refLocation": "b43/1",
"section": "Discussion",
"snippet": "The exposure of preadipocytes to pro-inflammatory cytokines inhibits adipogenesis by reducing the expression of Pparg and inhibiting the adipogenic action of insulin <cite data-doi=\"10.1038/ncb942\">28</cite> . Th1 cytokines, including IFN-γ, can inhibit insulin signalling and lipid droplet formation <cite data-doi=\"10.1074/jbc.m109.061655\">27,</cite><cite data-doi=\"10.1194/jlr.m008771\">42</cite> , while Th2 cytokines, including IL-4 and IL-13, can suppress inflammatory responses in adipose tissue <cite data-doi=\"10.1038/nri2921\">43</cite> . The increased expression of Ifng and decreased expression of Il4 and Il13 in the perigonadal fat of HFD-fed ΔdblGATA mice imply that the microenvironments of the WAT of these mice are unfavourable for adipocyte maturation.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1038/nri2921"
},
{
"refLocation": "b22/2",
"section": "Discussion",
"snippet": "Obesity is associated with an increased infiltration of macrophages, preferentially the pro-inflammatory M1 phenotype, into adipose tissue <cite data-doi=\"10.1172/jci19246\">22</cite> , and IL-4 produced by adipose tissue eosinophils supports the polarization of anti-inflammatory M2 macrophages <cite data-doi=\"10.1126/science.1201475\">5</cite> . In agreement this with this idea, conditioned media (CM) collected from eosinophilic cell line EoL-1 cells or CM from palmitic-acid stimulated EoL-1 cells promoted M2-polarization of monocytic THP-1 cells (Fig.",
"source": "10.1038/s41598-018-28371-4",
"target": "10.1172/jci19246"
},
{
"refLocation": "b4/3",
"section": "Discussion",
"snippet": "Obesity is associated with an increased infiltration of macrophages, preferentially the pro-inflammatory M1 phenotype, into adipose tissue <cite data-doi=\"10.1172/jci19246\">22</cite> , and IL-4 produced by adipose tissue eosinophils supports the polarization of anti-inflammatory M2 macrophages <cite data-doi=\"10.1126/science.1201475\">5</cite> . In agreement this with this idea, conditioned media (CM) collected from eosinophilic cell line EoL-1 cells or CM from palmitic-acid stimulated EoL-1 cells promoted M2-polarization of monocytic THP-1 cells (Fig.",
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"snippet": "5). Given that hypoxia induces macrophage proliferation and polarization towards the M2 phenotype <cite data-doi=\"10.1002/ijc.21422\">44,</cite><cite data-doi=\"10.1080/2162402x.2015.1056442\">45</cite> , it is plausible that hypoxia determined the composition of macrophages in the adipose tissue of HFD-fed ΔdblGATA mice. The significantly elevated concentration of lactate in the perigonadal WAT of HFD-fed ΔdblGATA mice also supports this idea (Fig.",
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"snippet": "5). Given that hypoxia induces macrophage proliferation and polarization towards the M2 phenotype <cite data-doi=\"10.1002/ijc.21422\">44,</cite><cite data-doi=\"10.1080/2162402x.2015.1056442\">45</cite> , it is plausible that hypoxia determined the composition of macrophages in the adipose tissue of HFD-fed ΔdblGATA mice. The significantly elevated concentration of lactate in the perigonadal WAT of HFD-fed ΔdblGATA mice also supports this idea (Fig.",
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"section": "Discussion",
"snippet": "Although adipose tissue is rich in stem cells that can differentiate into fat cells to contain excess energy <cite data-doi=\"10.1091/mbc.e02-02-0105\">46</cite> , the pro-inflammatory microenvironment of adipose tissue induced by obesity is associated with the inhibition of adipocyte maturation and increased adipocyte death <cite data-doi=\"10.1172/jci31021\">10,</cite><cite data-doi=\"10.1038/ijo.2008.229\">12</cite> . Our data demonstrate that adipocytes provide signals to promote eosinophil migration and survival, and that eosinophils support adipocyte maturation and protect adipose tissue against inflammatory changes.",
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"section": "Discussion",
"snippet": "Although adipose tissue is rich in stem cells that can differentiate into fat cells to contain excess energy <cite data-doi=\"10.1091/mbc.e02-02-0105\">46</cite> , the pro-inflammatory microenvironment of adipose tissue induced by obesity is associated with the inhibition of adipocyte maturation and increased adipocyte death <cite data-doi=\"10.1172/jci31021\">10,</cite><cite data-doi=\"10.1038/ijo.2008.229\">12</cite> . Our data demonstrate that adipocytes provide signals to promote eosinophil migration and survival, and that eosinophils support adipocyte maturation and protect adipose tissue against inflammatory changes.",
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"refLocation": "b12/1",
"section": "Discussion",
"snippet": "Although adipose tissue is rich in stem cells that can differentiate into fat cells to contain excess energy <cite data-doi=\"10.1091/mbc.e02-02-0105\">46</cite> , the pro-inflammatory microenvironment of adipose tissue induced by obesity is associated with the inhibition of adipocyte maturation and increased adipocyte death <cite data-doi=\"10.1172/jci31021\">10,</cite><cite data-doi=\"10.1038/ijo.2008.229\">12</cite> . Our data demonstrate that adipocytes provide signals to promote eosinophil migration and survival, and that eosinophils support adipocyte maturation and protect adipose tissue against inflammatory changes.",
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"section": "Method",
"snippet": "RNA isolated from the small intestine of 8-10-week-old WT (n = 4) and ∆dblGATA mice (n = 4) was subjected to RNA sequencing at the Cincinnati Children's Hospital Medical Center sequencing core. Sequencing data were demultiplexed and reads were mapped to the mm10 mouse genome reference using TopHat <cite data-doi=\"10.1093/bioinformatics/btp120\">47</cite> . The total number of mapped reads per transcript was determined and the data were normalized to detect the number of fragments per kilobase of exon per million fragments mapped (FPKM) using Cufflinks <cite data-doi=\"10.1038/nbt.1621\">48</cite> .",
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"refLocation": "b48/1",
"section": "Method",
"snippet": "Sequencing data were demultiplexed and reads were mapped to the mm10 mouse genome reference using TopHat <cite data-doi=\"10.1093/bioinformatics/btp120\">47</cite> . The total number of mapped reads per transcript was determined and the data were normalized to detect the number of fragments per kilobase of exon per million fragments mapped (FPKM) using Cufflinks <cite data-doi=\"10.1038/nbt.1621\">48</cite> . An FPKM >0.1 in at least 1 of the analysed samples was used to filter for potentially significant gene expression.",
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"refLocation": "b50/1",
"section": "Method",
"snippet": "Insulin (0.75 U/kg) or saline was infused into the liver via the portal vein. Five minutes after infusion, liver, perigonadal fat, and skeletal muscle were quickly excised and snap-frozen in liquid nitrogen <cite data-doi=\"10.1002/hep.26015\">50</cite> . At sacrifice, all mice were weighed and the livers and perigonadal fat were removed and weighed.",
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"target": "10.1002/hep.26015"
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"refLocation": "b50/2",
"section": "Method",
"snippet": "Total protein extraction and western blot analysis. The tissue lysates were prepared in ice-cold tissue lysis buffer (50 mM Tris-HCl, pH 7.5; 150 mM NaCl; 1% Nonidet P-40; 0.5% sodium deoxycholate; 0.1% SDS) containing 50 mM NaF, 2 mM Na 3 VO 4 , protease inhibitors (Sigma-Aldrich, St. Louis, MO, USA) and phosphatase inhibitors (Sigma-Aldrich) and total protein was extracted as previously described <cite data-doi=\"10.1002/hep.26015\">50</cite> . Samples from tissue lysates were resolved by SDS-PAGE and then transferred to a nitrocellulose membrane.",
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"target": "10.1002/hep.26015"
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"refLocation": "b20/2",
"section": "Isolation of eosinophils.",
"snippet": "Eosinophils were isolated from the peritoneal cavity of CD3-IL-5 transgenic mice as described <cite data-doi=\"10.1038/s41598-017-06397-4\">20</cite> and used for chemotaxis assay and co-culture with adipocyte-differentiated 3T3-L1 cells. Total cells were extracted and subjected to lymphocyte depletion using a MACS ® system with antibodies against CD90.2 and CD45R (Miltenyi Biotec, Auburn, CA, USA).",
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"abstract": "Accumulating data have indicated a fundamental role of eosinophils in regulating adipose tissue homeostasis. Here, we performed whole-genome RNA sequencing of the small intestinal tract, which suggested the presence of impaired lipid metabolism in eosinophil-deficient ΔdblGATA mice. ΔdblGATA mice fed a high-fat diet (HFD) showed reduced body fat mass, impaired enlargement of adipocytes, decreased expression of adipogenic genes, and developed glucose intolerance. HFD induced accumulation of eosinophils in the perigonadal white adipose tissue. Concordantly, adipocytedifferentiated 3T3-L1 cells promoted the migration of eosinophils through the expression of CCL11 (eotaxin-1) and likely promoted their survival through the expression of interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor. HFD-fed ΔdblGATA mice showed increased infiltration of macrophages, CD4 + T-cells, and B-cells, increased expression of interferon-γ, and decreased expression of IL-4 and IL-13 in white adipose tissue. Interferon-γ treatment significantly decreased lipid deposition in adipocyte-differentiated 3T3-L1 cells, while IL-4 treatment promoted lipid accumulation. Notably, HFD-fed ΔdblGATA mice showed increased lipid storage in the liver as compared with wild-type mice. We propose that obesity promotes the infiltration of eosinophils into adipose tissue that subsequently contribute to the metabolic homeostasis by promoting adipocyte maturation.Eosinophils have been considered as destructive cells involved in T helper cell type (Th) 2 immune responses in parasitic infections or allergic diseases 1 . However, accumulating evidence has indicated additional roles for eosinophils. For example, eosinophils reside in several organs including the gastrointestinal tract 2,3 and adipose tissue and contribute to metabolic homeostasis 4,5 . Adipose tissue eosinophils secrete interleukin (IL)-4 and induce the polarization of white adipose tissue (WAT) macrophages into alternatively-activated macrophages, which support glucose tolerance by regulating local catecholamine stores in the microenvironment through the import of catecholamines produced by nerve cells 4,6,7 . Despite recent advances, the roles of eosinophils in the adipose tissue and their effects on adipocyte function remain incompletely understood.Obesity and its associated metabolic disorders are serious health problems worldwide 8 . However, obesity is not necessarily an adverse metabolic condition when the excess fat is stored in adipose tissue that responds to insulin 9 . Adipose tissue regulates energy homeostasis through the storage of excess calories and the secretion of adipocyte-derived secretory proteins such as leptin, adiponectin, and resistin 10,11 . However, excessive caloric Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 SCIentIfIC REPORTS | (2018) 8:9894 | intake induces the overexpansion of adipocytes, which results in inflammatory responses within adipose tissue 12 .Obesity-related metabolic dysfunctions are associated with an excessiv...",
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"family": "Itan",
"given": "Michal"
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"family": "Jang",
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"family": "Gu",
"given": "Hyeon-Jung"
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"family": "Rozenberg",
"given": "Perri"
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"family": "Mingler",
"given": "Melissa"
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"family": "Wen",
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"family": "Yoon",
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{
"family": "Munitz",
"given": "Ariel"
},
{
"family": "Jung",
"given": "Yunjae"
}
],
"keywords": [],
"title": "Eosinophils support adipocyte maturation and promote glucose tolerance in obesity OPEN"
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