{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:53:18Z","timestamp":1791406398047,"version":"4.3.3"},"reference-count":38,"publisher":"American Diabetes Association","issue":"8","license":[{"start":{"date-parts":[[2017,2,1]],"date-time":"2017-02-01T00:00:00Z","timestamp":1485907200000},"content-version":"vor","delay-in-days":264,"URL":"http:\/\/www.diabetesjournals.org\/site\/license"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["K08-DK-100543"],"award-info":[{"award-number":["K08-DK-100543"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,8,1]]},"abstract":"<jats:p>To determine the roles of insulin and insulin-like growth factor 1 (IGF-1) action in adipose tissue, we created mice lacking the insulin receptor (IR), IGF-1 receptor (IGF1R), or both using Cre-recombinase driven by the adiponectin promoter. Mice lacking IGF1R only (F-IGFRKO) had a \u223c25% reduction in white adipose tissue (WAT) and brown adipose tissue (BAT), whereas mice lacking both IR and IGF1R (F-IR\/IGFRKO) showed an almost complete absence of WAT and BAT. Interestingly, mice lacking only the IR (F-IRKO) had a 95% reduction in WAT, but a paradoxical 50% increase in BAT with accumulation of large unilocular lipid droplets. Both F-IRKO and F-IR\/IGFRKO mice were unable to maintain body temperature in the cold and developed severe diabetes, ectopic lipid accumulation in liver and muscle, and pancreatic islet hyperplasia. Leptin treatment normalized blood glucose levels in both groups. Glucose levels also improved spontaneously by 1 year of age, despite sustained lipodystrophy and insulin resistance. Thus, loss of IR is sufficient to disrupt white fat formation, but not brown fat formation and\/or maintenance, although it is required for normal BAT function and temperature homeostasis. IGF1R has only a modest contribution to both WAT and BAT formation and function.<\/jats:p>","DOI":"10.2337\/db16-0212","type":"journal-article","created":{"date-parts":[[2016,5,14]],"date-time":"2016-05-14T05:26:15Z","timestamp":1463203575000},"page":"2201-2213","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":149,"title":["Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function"],"prefix":"10.2337","volume":"65","author":[{"given":"Jeremie","family":"Boucher","sequence":"first","affiliation":[{"name":"Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Softic","sequence":"additional","affiliation":[{"name":"Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA"},{"name":"Division of Gastroenterology, Hepatology and Nutrition, Boston Children\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelfattah","family":"El Ouaamari","sequence":"additional","affiliation":[{"name":"Islet Cell and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan T.","family":"Krumpoch","sequence":"additional","affiliation":[{"name":"Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Kleinridders","sequence":"additional","affiliation":[{"name":"Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit N.","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Islet Cell and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian T.","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Ronald","family":"Kahn","sequence":"additional","affiliation":[{"name":"Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2016,5,13]]},"reference":[{"key":"2022031300043159500_B1","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.beem.2005.07.011","article-title":"Insulin-like growth factor I, growth hormone and insulin in white adipose tissue","volume":"19","author":"Bl\u00fcher","year":"2005","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2022031300043159500_B2","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.mce.2009.12.011","article-title":"The development and endocrine functions of adipose tissue","volume":"323","author":"Poulos","year":"2010","journal-title":"Mol Cell Endocrinol"},{"key":"2022031300043159500_B3","doi-asserted-by":"crossref","first-page":"17235","DOI":"10.1074\/jbc.M110.118620","article-title":"Insulin and insulin-like growth factor-1 receptors act as ligand-specific amplitude modulators of a common pathway regulating gene transcription","volume":"285","author":"Boucher","year":"2010","journal-title":"J Biol Chem"},{"key":"2022031300043159500_B4","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fendo.2012.00034","article-title":"Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances","volume":"3","author":"Siddle","year":"2012","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2022031300043159500_B5","doi-asserted-by":"crossref","first-page":"38016","DOI":"10.1074\/jbc.M313201200","article-title":"Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I","volume":"279","author":"Entingh-Pearsall","year":"2004","journal-title":"J Biol Chem"},{"key":"2022031300043159500_B6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1534-5807(02)00199-5","article-title":"Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance","volume":"3","author":"Bl\u00fcher","year":"2002","journal-title":"Dev Cell"},{"key":"2022031300043159500_B7","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":"2022031300043159500_B8","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":"2022031300043159500_B9","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":"2022031300043159500_B10","doi-asserted-by":"crossref","first-page":"864","DOI":"10.2337\/db12-1089","article-title":"Lessons on conditional gene targeting in mouse adipose tissue","volume":"62","author":"Lee","year":"2013","journal-title":"Diabetes"},{"key":"2022031300043159500_B11","doi-asserted-by":"crossref","first-page":"206","DOI":"10.4161\/adip.29674","article-title":"Characterization of Cre recombinase models for the study of adipose tissue","volume":"3","author":"Jeffery","year":"2014","journal-title":"Adipocyte"},{"key":"2022031300043159500_B12","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.cmet.2011.02.005","article-title":"Transcriptional control of adipose lipid handling by IRF4","volume":"13","author":"Eguchi","year":"2011","journal-title":"Cell Metab"},{"key":"2022031300043159500_B13","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1210\/me.2012-1267","article-title":"A novel adipose-specific gene deletion model demonstrates potential pitfalls of existing methods","volume":"27","author":"Mullican","year":"2013","journal-title":"Mol Endocrinol"},{"key":"2022031300043159500_B14","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.celrep.2013.01.007","article-title":"Liver-derived systemic factors drive \u03b2 cell hyperplasia in insulin-resistant states","volume":"3","author":"El Ouaamari","year":"2013","journal-title":"Cell Reports"},{"key":"2022031300043159500_B15","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1016\/j.celrep.2015.04.037","article-title":"Differential Role of Insulin\/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis","volume":"11","author":"O\u2019Neill","year":"2015","journal-title":"Cell Reports"},{"key":"2022031300043159500_B16","doi-asserted-by":"crossref","first-page":"10989","DOI":"10.1074\/jbc.M113.527002","article-title":"Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis","volume":"289","author":"Debosch","year":"2014","journal-title":"J Biol Chem"},{"key":"2022031300043159500_B17","doi-asserted-by":"crossref","first-page":"4408","DOI":"10.1096\/fj.14-253971","article-title":"Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications","volume":"28","author":"Vernochet","year":"2014","journal-title":"FASEB J"},{"key":"2022031300043159500_B18","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/43448","article-title":"Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy","volume":"401","author":"Shimomura","year":"1999","journal-title":"Nature"},{"key":"2022031300043159500_B19","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.2337\/diabetes.50.6.1440","article-title":"Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes","volume":"50","author":"Ebihara","year":"2001","journal-title":"Diabetes"},{"key":"2022031300043159500_B20","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1172\/JCI200419511","article-title":"Site and mechanism of leptin action in a rodent form of congenital lipodystrophy","volume":"113","author":"Asilmaz","year":"2004","journal-title":"J Clin Invest"},{"key":"2022031300043159500_B21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nrendo.2010.199","article-title":"Lipodystrophy: pathophysiology and advances in treatment","volume":"7","author":"Fiorenza","year":"2011","journal-title":"Nat Rev Endocrinol"},{"key":"2022031300043159500_B22","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.cell.2013.04.008","article-title":"Betatrophin: a hormone that controls pancreatic \u03b2 cell proliferation","volume":"153","author":"Yi","year":"2013","journal-title":"Cell"},{"key":"2022031300043159500_B23","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.cell.2014.09.027","article-title":"ANGPTL8\/betatrophin does not control pancreatic beta cell expansion","volume":"159","author":"Gusarova","year":"2014","journal-title":"Cell"},{"key":"2022031300043159500_B24","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.cmet.2015.12.001","article-title":"SerpinB1 Promotes Pancreatic \u03b2 Cell Proliferation","volume":"23","author":"El Ouaamari","year":"2016","journal-title":"Cell Metab"},{"key":"2022031300043159500_B25","first-page":"2187","article-title":"Lipodystrophy due to adipose tissue\u2013specific insulin receptor knockout results in progressive NAFLD","author":"Softic","year":"2016"},{"key":"2022031300043159500_B26","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/78693","article-title":"Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance","volume":"6","author":"Zisman","year":"2000","journal-title":"Nat Med"},{"key":"2022031300043159500_B27","doi-asserted-by":"crossref","first-page":"983","DOI":"10.2337\/diab.46.6.983","article-title":"Skeletal muscle triglyceride levels are inversely related to insulin action","volume":"46","author":"Pan","year":"1997","journal-title":"Diabetes"},{"key":"2022031300043159500_B28","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1073\/pnas.71.1.84","article-title":"Insulin-dependent regulation of insulin receptor concentrations: a direct demonstration in cell culture","volume":"71","author":"Gavin","year":"1974","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022031300043159500_B29","doi-asserted-by":"crossref","first-page":"S262","DOI":"10.2337\/dc08-s264","article-title":"Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?","volume":"31","author":"Shanik","year":"2008","journal-title":"Diabetes Care"},{"key":"2022031300043159500_B30","doi-asserted-by":"crossref","first-page":"26746","DOI":"10.1074\/jbc.270.45.26746","article-title":"A novel serum protein similar to C1q, produced exclusively in adipocytes","volume":"270","author":"Scherer","year":"1995","journal-title":"J Biol Chem"},{"key":"2022031300043159500_B31","doi-asserted-by":"crossref","first-page":"10697","DOI":"10.1074\/jbc.271.18.10697","article-title":"AdipoQ is a novel adipose-specific gene dysregulated in obesity","volume":"271","author":"Hu","year":"1996","journal-title":"J Biol Chem"},{"key":"2022031300043159500_B32","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.bbrc.2005.09.064","article-title":"Adiponectin expression in humans is dependent on differentiation of adipocytes and down-regulated by humoral serum components of high molecular weight","volume":"337","author":"K\u00f6rner","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031300043159500_B33","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1038\/nm.3324","article-title":"Tracking adipogenesis during white adipose tissue development, expansion and regeneration","volume":"19","author":"Wang","year":"2013","journal-title":"Nat Med"},{"key":"2022031300043159500_B34","doi-asserted-by":"crossref","first-page":"15712","DOI":"10.1073\/pnas.2536828100","article-title":"Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle","volume":"100","author":"He","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022031300043159500_B35","doi-asserted-by":"crossref","first-page":"6207","DOI":"10.1073\/pnas.0306743102","article-title":"Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance","volume":"102","author":"Jones","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022031300043159500_B36","doi-asserted-by":"crossref","first-page":"18656","DOI":"10.1073\/pnas.1314863110","article-title":"Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPAR\u03b3","volume":"110","author":"Wang","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022031300043159500_B37","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1677\/JOE-10-0272","article-title":"Lipodystrophy: metabolic insights from a rare disorder","volume":"207","author":"Huang-Doran","year":"2010","journal-title":"J Endocrinol"},{"key":"2022031300043159500_B38","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1172\/JCI0215001","article-title":"Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy","volume":"109","author":"Petersen","year":"2002","journal-title":"J Clin Invest"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db16-0212","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/65\/8\/2201\/582111\/db160212.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/65\/8\/2201\/582111\/db160212.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:50:05Z","timestamp":1667407805000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/65\/8\/2201\/35147\/Differential-Roles-of-Insulin-and-IGF-1-Receptors"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,13]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2016,5,13]]},"published-print":{"date-parts":[[2016,8,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db16-0212","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,13]]}}}