{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:45:21Z","timestamp":1778780721733,"version":"3.51.4"},"reference-count":35,"publisher":"The Endocrine Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Brown fat is a thermogenic tissue that generates heat to maintain body temperature in cold environments and dissipate excess energy in response to overfeeding. We have addressed the role of the IGFIR in the brown fat development and function. Mice lacking IGFIR exhibited normal brown adipose tissue\/body weight in knockout (KO) vs control mice. However, lack of IGFIR decreased uncoupling protein 1 expression in interscapular brown fat and beige cells in inguinal fat. More importantly, the lack of IGFIR resulted in an impaired cold acclimation. No differences in the total fat volume were found in the KO vs control mice. Epididymal fat showed larger adipocytes but with a lower number of adipocytes in KO vs control mice at age 12 months. In addition, KO mice showed a sustained moderate hyperinsulinemia and hypertriglyceridemia upon time and hepatic insulin insensitivity associated with lipid accumulation, with the outcome of a global insulin resistance. In addition, we found that the expression of uncoupling protein 3 in the skeletal muscle was decreased and its expression was increased in the heart in parallel with the expression of beta-2 adrenergic receptors. Upon nonobesogenic high-fat diet, we found a severe insulin resistance in the liver and in the skeletal muscle, but unchanged insulin sensitivity in the heart. In conclusion, our data suggest that IGFIR it is not an essential growth factor in the brown fat development in the presence of the IR and very high plasma levels of IGF-I, but it is indispensable for full brown fat functionality.<\/jats:p>","DOI":"10.1210\/en.2015-1623","type":"journal-article","created":{"date-parts":[[2016,2,24]],"date-time":"2016-02-24T22:02:17Z","timestamp":1456351337000},"page":"1495-1511","source":"Crossref","is-referenced-by-count":15,"title":["Essential Role of IGFIR in the Onset of Male Brown Fat Thermogenic Function: Regulation of Glucose Homeostasis by Differential Organ-Specific Insulin Sensitivity"],"prefix":"10.1210","volume":"157","author":[{"given":"Vanesa","family":"Viana-Huete","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University\u2013Madrid, Madrid 28040, Spain"},{"name":"Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Guill\u00e9n","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University\u2013Madrid, Madrid 28040, Spain"},{"name":"Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Garc\u00eda-Aguilar","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University\u2013Madrid, Madrid 28040, Spain"},{"name":"Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gema","family":"Garc\u00eda","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University\u2013Madrid, Madrid 28040, Spain"},{"name":"Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University\u2013Madrid, Madrid 28040, Spain"},{"name":"Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. R.","family":"Kahn","sequence":"first","affiliation":[{"name":"Joslin Diabetes Center (C.R.K.), Harvard Medical School, Boston, MA 02215"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Benito","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Complutense University\u2013Madrid, Madrid 28040, Spain"},{"name":"Spanish Diabetes and Metabolic Research Network (V.V.-H., C.G., A.G.-A., G.G., S.F., M.B.), Institute of Health Carlos III, Madrid 28029, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2016,2,24]]},"reference":[{"key":"2020071611580863100_B1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1152\/physrev.00015.2003","article-title":"Brown adipose tissue: Function and physiological significance","volume":"84","author":"Cannon","year":"2004","journal-title":"Physiol Rev"},{"key":"2020071611580863100_B2","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/366740a0","article-title":"Development of obesity in transgenic mice after genetic ablation of brown adipose tissue","volume":"366","author":"Lowell","year":"1993","journal-title":"Nature"},{"key":"2020071611580863100_B3","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.cmet.2008.12.014","article-title":"UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality","volume":"9","author":"Feldmann","year":"2009","journal-title":"Cell Metab"},{"key":"2020071611580863100_B4","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1056\/NEJMoa0810780","article-title":"Identification and importance of brown adipose tissue in adult humans","volume":"360","author":"Cypess","year":"2009","journal-title":"N Engl J Med"},{"key":"2020071611580863100_B5","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.2337\/db09-0530","article-title":"High incidence of metabolically active brown adipose tissue in healthy adult humans: Effects of cold exposure and adiposity","volume":"58","author":"Saito","year":"2009","journal-title":"Diabetes"},{"key":"2020071611580863100_B6","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1056\/NEJMoa0808718","article-title":"Cold-activated brown adipose tissue in healthy men","volume":"360","author":"van Marken Lichtenbelt","year":"2009","journal-title":"N Engl J Med"},{"key":"2020071611580863100_B7","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1056\/NEJMoa0808949","article-title":"Functional brown adipose tissue in healthy adults","volume":"360","author":"Virtanen","year":"2009","journal-title":"N Engl J Med"},{"key":"2020071611580863100_B8","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1096\/fj.09-133546","article-title":"The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue","volume":"23","author":"Zingaretti","year":"2009","journal-title":"FASEB J"},{"key":"2020071611580863100_B9","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.cell.2013.12.021","article-title":"Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch","volume":"156","author":"Cohen","year":"2014","journal-title":"Cell"},{"key":"2020071611580863100_B10","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1038\/nature07221","article-title":"New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure","volume":"454","author":"Tseng","year":"2008","journal-title":"Nature"},{"key":"2020071611580863100_B11","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1172\/JCI13103","article-title":"Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance","volume":"108","author":"Guerra","year":"2001","journal-title":"J. Clin Invest"},{"key":"2020071611580863100_B12","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1210\/en.2011-1765","article-title":"Brown fat lipoatrophy and increased visceral adiposity through a concerted adipocytokines overexpression induces vascular insulin resistance and dysfunction","volume":"153","author":"G\u00f3mez-Hern\u00e1ndez","year":"2012","journal-title":"Endocrinology"},{"key":"2020071611580863100_B13","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1038\/ncomms1905","article-title":"Impaired thermogenesis and adipose tissue development in mice with fat-specific disruption of insulin and IGF-1 signalling","volume":"3","author":"Boucher","year":"2012","journal-title":"Nat Commun"},{"key":"2020071611580863100_B14","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ng872","article-title":"\u03b2-cell\u2013specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter \u03b2-cell mass","volume":"31","author":"Kulkarni","year":"2002","journal-title":"Nat Genet"},{"key":"2020071611580863100_B15","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S1097-2765(00)80155-0","article-title":"A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance","volume":"2","author":"Br\u00fcning","year":"1998","journal-title":"Molec Cell"},{"key":"2020071611580863100_B16","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1210\/mend.12.5.0106","article-title":"Insulin receptor substrate (IRS) proteins IRS-1 and IRS-2 differential signaling in the insulin\/insulin-like growth factor-I pathways in fetal brown adipocytes","volume":"12","author":"Valverde","year":"1998","journal-title":"Molec Endocrinol"},{"key":"2020071611580863100_B17","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.cmet.2014.08.002","article-title":"Obesity-induced CerS6-dependent C16:0 Ceramide production promotes weight gain and glucose intolerance","volume":"20","author":"Turpin","year":"2014","journal-title":"Cell Metab"},{"key":"2020071611580863100_B18","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real time quantitative PCR and the 2\u2212\u0394\u0394Ct method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2020071611580863100_B19","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.2337\/db10-0771","article-title":"G protein-coupled receptor kinase 2 plays a relevant role in insulin resistance and obesity","volume":"59","author":"Garcia-Guerra","year":"2010","journal-title":"Diabetes"},{"key":"2020071611580863100_B20","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1038\/nprot.2013.055","article-title":"Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease","volume":"8","author":"Mehlem","year":"2013","journal-title":"Nat Protoc"},{"key":"2020071611580863100_B21","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1002\/jcb.24577","article-title":"Concerted expression of the thermogenic and bioenergetic mitochondrial protein machinery in brown adipose tissue","volume":"114","author":"Guillen","year":"2013","journal-title":"J Cell Biochem"},{"key":"2020071611580863100_B22","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1172\/JCI0213503","article-title":"Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle","volume":"109","author":"Fern\u00e1ndez","year":"2002","journal-title":"J. Clin Invest"},{"key":"2020071611580863100_B23","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.2337\/db07-1538","article-title":"Autocrine IGF-1 action in adipocytes controls systemic IGF-1 concentrations and growth","volume":"57","author":"Kl\u00f6ting","year":"2008","journal-title":"Diabetes"},{"key":"2020071611580863100_B24","doi-asserted-by":"crossref","first-page":"743","DOI":"10.2337\/diabetes.51.3.743","article-title":"Increased insulin sensitivity in IGF-I receptor\u2013deficient brown adipocytes","volume":"51","author":"Mur","year":"2002","journal-title":"Diabetes"},{"key":"2020071611580863100_B25","doi-asserted-by":"crossref","first-page":"820","DOI":"10.2337\/db08-0551","article-title":"\u03b2-Cell hyperplasia induced by hepatic insulin resistance: Role of a liver-pancreas endocrine axis through insulin receptor A isoform","volume":"58","author":"Escribano","year":"2009","journal-title":"Diabetes"},{"key":"2020071611580863100_B26","doi-asserted-by":"crossref","first-page":"352","DOI":"10.2741\/s156","article-title":"Physiological importance and control of non-shivering facultative thermogenesis","volume":"25","author":"Silva","year":"2011","journal-title":"Front Biosci (Schol Ed)"},{"key":"2020071611580863100_B27","doi-asserted-by":"crossref","first-page":"13087","DOI":"10.1074\/jbc.M800533200","article-title":"Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis","volume":"283","author":"Reid","year":"2008","journal-title":"J Biol Chem"},{"key":"2020071611580863100_B28","first-page":"108","article-title":"Antagonistic effect of TNF-alpha and insulin on uncoupling protein 2 (UCP-2) expression and vascular damage","volume":"13","author":"G\u00f3mez-Hern\u00e1ndez","year":"2014","journal-title":"Cardiovasc Diabetol"},{"key":"2020071611580863100_B29","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1210\/jc.2005-1572","article-title":"Reduced skeletal muscle uncoupling protein-3 content in prediabetic subjects and type 2 diabetic patients: Restoration by rosiglitazone treatment","volume":"91","author":"Schrauwen","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071611580863100_B30","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1038\/nm.2897","article-title":"Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals","volume":"18","author":"Bal","year":"2012","journal-title":"Nat Med"},{"key":"2020071611580863100_B31","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s00395-011-0156-1","article-title":"A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart","volume":"106","author":"Cole","year":"2011","journal-title":"Basic Res Cardiol"},{"key":"2020071611580863100_B32","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.2337\/diabetes.54.8.2343","article-title":"Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells","volume":"54","author":"MacLellan","year":"2005","journal-title":"Diabetes"},{"key":"2020071611580863100_B33","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1253\/circj.CJ-14-1080","article-title":"Insulin Regulation of Myocardial Autophagy","volume":"78","author":"Riehle","year":"2014","journal-title":"Circ J"},{"key":"2020071611580863100_B34","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s12192-010-0185-y","article-title":"Expression of uncoupling protein 3 in mitochondria protects against stress-induced myocardial injury: A proteomic study","volume":"15","author":"Wang","year":"2010","journal-title":"Cell Stress Chaperones"},{"key":"2020071611580863100_B35","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1016\/j.febslet.2005.02.022","article-title":"Thyroid-hormone effects on putative biochemical pathways involved in UCP3 activation in rat skeletal muscle mitochondria","volume":"579","author":"Silvestri","year":"2005","journal-title":"FEBS Letters"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/157\/4\/1495\/8994536\/endo1495.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/157\/4\/1495\/8994536\/endo1495.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T18:14:03Z","timestamp":1594923243000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/157\/4\/1495\/2422523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2,24]]},"references-count":35,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2016,4,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2015-1623","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,2,24]]}}}