{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T22:45:30Z","timestamp":1785451530689,"version":"3.56.0"},"reference-count":41,"publisher":"American Diabetes Association","issue":"1","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":3546,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,1,1]]},"abstract":"<jats:sec>\n                  <jats:title\/>\n                  <jats:p>Reproductive dysfunction is associated with obesity. We previously showed that female mice with diet-induced obesity (DIO) exhibit infertility and thus serve as a model of human polycystic ovary syndrome (PCOS). We postulated that differential insulin signaling of tissues leads to reproductive dysfunction; therefore, a comparison of insulin signaling in reproductive tissues and energy storage tissues was performed. Pituitary-specific insulin receptor knockout mice were used as controls. High-fat diet\u2013induced stress, which leads to insulin resistance, was also investigated by assaying macrophage infiltration and phosphorylated Jun NH2-terminal kinase (pJNK) signaling. In lean mice, reproductive tissues exhibited reduced sensitivity to insulin compared with peripheral metabolic tissues. However, in obese mice, where metabolic tissues exhibited insulin resistance, the pituitary and ovary maintained insulin sensitivity. Pituitaries responded to insulin through insulin receptor substrate (IRS)2 but not IRS1, whereas in the ovary, both IRS1 and IRS2 were activated by insulin. Macrophage infiltration and pJNK signaling were not increased in the pituitary or ovary of lean mice relative to DIO mice. The lack of inflammation and cytokine signaling in the pituitary and ovary in DIO mice compared with lean mice may be one of the reasons that these tissues remained insulin sensitive. Retained sensitivity of the pituitary and ovary to insulin may contribute to the pathophysiology of PCOS.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db11-0956","type":"journal-article","created":{"date-parts":[[2011,11,11]],"date-time":"2011-11-11T02:59:44Z","timestamp":1320980384000},"page":"114-123","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":53,"title":["Reproductive Tissues Maintain Insulin Sensitivity in Diet-Induced Obesity"],"prefix":"10.2337","volume":"61","author":[{"given":"Sheng","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Divall","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredric","family":"Wondisford","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Wolfe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2011,12,12]]},"reference":[{"key":"2022031210271280700_B1","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1056\/NEJMra041536","article-title":"Polycystic ovary syndrome","volume":"352","author":"Ehrmann","year":"2005","journal-title":"N Engl J Med"},{"key":"2022031210271280700_B2","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.cmet.2010.06.010","article-title":"Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor","volume":"12","author":"Brothers","year":"2010","journal-title":"Cell Metab"},{"key":"2022031210271280700_B3","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/35030105","article-title":"IRS-2 pathways integrate female reproduction and energy homeostasis","volume":"407","author":"Burks","year":"2000","journal-title":"Nature"},{"key":"2022031210271280700_B4","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1523\/JNEUROSCI.2974-10.2011","article-title":"Jak2 is necessary for neuroendocrine control of female reproduction","volume":"31","author":"Wu","year":"2011","journal-title":"J Neurosci"},{"key":"2022031210271280700_B5","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.bbrc.2007.10.007","article-title":"IRS-1 transgenic mice show increased epididymal fat mass and insulin resistance","volume":"364","author":"Murata","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031210271280700_B6","doi-asserted-by":"crossref","first-page":"935","DOI":"10.2337\/db09-0404","article-title":"Neutralization of osteopontin inhibits obesity-induced inflammation and insulin resistance","volume":"59","author":"Kiefer","year":"2010","journal-title":"Diabetes"},{"key":"2022031210271280700_B7","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature01137","article-title":"A central role for JNK in obesity and insulin resistance","volume":"420","author":"Hirosumi","year":"2002","journal-title":"Nature"},{"key":"2022031210271280700_B8","doi-asserted-by":"crossref","first-page":"E413","DOI":"10.1152\/ajpendo.00514.2001","article-title":"IRS proteins and the common path to diabetes","volume":"283","author":"White","year":"2002","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022031210271280700_B9","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1139\/y06-008","article-title":"Regulating insulin signaling and beta-cell function through IRS proteins","volume":"84","author":"White","year":"2006","journal-title":"Can J Physiol Pharmacol"},{"key":"2022031210271280700_B10","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1172\/JCI200319451","article-title":"Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance","volume":"112","author":"Xu","year":"2003","journal-title":"J Clin Invest"},{"key":"2022031210271280700_B11","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1172\/JCI200319246","article-title":"Obesity is associated with macrophage accumulation in adipose tissue","volume":"112","author":"Weisberg","year":"2003","journal-title":"J Clin Invest"},{"key":"2022031210271280700_B12","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.coph.2009.07.004","article-title":"Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation","volume":"9","author":"Tanti","year":"2009","journal-title":"Curr Opin Pharmacol"},{"key":"2022031210271280700_B13","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1210\/en.2004-0767","article-title":"Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1 ser307 phosphorylation in a tissue-specific fashion","volume":"146","author":"Prada","year":"2005","journal-title":"Endocrinology"},{"key":"2022031210271280700_B14","doi-asserted-by":"crossref","first-page":"2900","DOI":"10.1172\/JCI41069","article-title":"Divergent roles of growth factors in the GnRH regulation of puberty in mice","volume":"120","author":"Divall","year":"2010","journal-title":"J Clin Invest"},{"key":"2022031210271280700_B15","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.1210\/en.2004-1520","article-title":"Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus","volume":"146","author":"De Souza","year":"2005","journal-title":"Endocrinology"},{"key":"2022031210271280700_B16","doi-asserted-by":"crossref","first-page":"13640","DOI":"10.1523\/JNEUROSCI.4023-08.2008","article-title":"Monitoring FoxO1 localization in chemically identified neurons","volume":"28","author":"Fukuda","year":"2008","journal-title":"J Neurosci"},{"key":"2022031210271280700_B17","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s00125-008-0929-8","article-title":"Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice","volume":"51","author":"Tsuneki","year":"2008","journal-title":"Diabetologia"},{"key":"2022031210271280700_B18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.mce.2009.07.014","article-title":"Insulin augments gonadotropin-releasing hormone induction of translation in LbetaT2 cells","volume":"311","author":"Navratil","year":"2009","journal-title":"Mol Cell Endocrinol"},{"key":"2022031210271280700_B19","doi-asserted-by":"crossref","first-page":"5030","DOI":"10.1210\/en.2010-0444","article-title":"Stimulatory effect of insulin on 5alpha-reductase type 1 (SRD5A1) expression through an Akt-dependent pathway in ovarian granulosa cells","volume":"151","author":"Kayampilly","year":"2010","journal-title":"Endocrinology"},{"key":"2022031210271280700_B20","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1210\/en.2003-0329","article-title":"Insulin augmentation of 17alpha-hydroxylase activity is mediated by phosphatidylinositol 3-kinase but not extracellular signal-regulated kinase-1\/2 in human ovarian theca cells","volume":"145","author":"Munir","year":"2004","journal-title":"Endocrinology"},{"key":"2022031210271280700_B21","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.2337\/dc08-0532","article-title":"First evidence of genetic association between AKT2 and polycystic ovary syndrome","volume":"31","author":"Goodarzi","year":"2008","journal-title":"Diabetes Care"},{"key":"2022031210271280700_B22","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1055\/s-0031-1273760","article-title":"Differential roles of MAPK-Erk1\/2 and MAPK-p38 in insulin or insulin-like growth factor-I (IGF-I) signaling pathways for progesterone production in human ovarian cells","volume":"43","author":"Seto-Young","year":"2011","journal-title":"Horm Metab Res"},{"key":"2022031210271280700_B23","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1677\/joe.1.06226","article-title":"Up-regulation of the phosphatidylinositol 3-kinase\/protein kinase B pathway in the ovary of rats by chronic treatment with hCG and insulin","volume":"190","author":"Lima","year":"2006","journal-title":"J Endocrinol"},{"key":"2022031210271280700_B24","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1177\/1933719108316389","article-title":"Peripubertal hyperinsulinemia upregulates phosphatidylinositol 3-kinase\/Akt pathway in rat ovaries","volume":"15","author":"Chakrabarty","year":"2008","journal-title":"Reprod Sci"},{"key":"2022031210271280700_B25","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1210\/jc.2007-2656","article-title":"Evidence for insulin suppression of baseline luteinizing hormone in women with polycystic ovarian syndrome and normal women","volume":"93","author":"Lawson","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031210271280700_B26","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1210\/endo-122-2-581","article-title":"The effects of experimental hyperinsulinemia on steroid secretion, ovarian [125I]insulin binding, and ovarian [125I]insulin-like growth-factor I binding in the rat","volume":"122","author":"Poretsky","year":"1988","journal-title":"Endocrinology"},{"key":"2022031210271280700_B27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1677\/JOE-09-0461","article-title":"Obesity induced by high-fat diet promotes insulin resistance in the ovary","volume":"206","author":"Akamine","year":"2010","journal-title":"J Endocrinol"},{"key":"2022031210271280700_B28","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1128\/MCB.01162-09","article-title":"Role of muscle c-Jun NH2-terminal kinase 1 in obesity-induced insulin resistance","volume":"30","author":"Sabio","year":"2010","journal-title":"Mol Cell Biol"},{"key":"2022031210271280700_B29","doi-asserted-by":"crossref","first-page":"45803","DOI":"10.1074\/jbc.M406963200","article-title":"Modulation of the JNK pathway in liver affects insulin resistance status","volume":"279","author":"Nakatani","year":"2004","journal-title":"J Biol Chem"},{"key":"2022031210271280700_B30","doi-asserted-by":"crossref","first-page":"6028","DOI":"10.1073\/pnas.1001796107","article-title":"Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism","volume":"107","author":"Belgardt","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022031210271280700_B31","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.jsbmb.2008.03.014","article-title":"Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic ovary syndrome (PCOS)","volume":"109","author":"Diamanti-Kandarakis","year":"2008","journal-title":"J Steroid Biochem Mol Biol"},{"key":"2022031210271280700_B32","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1210\/me.2009-0030","article-title":"ERK signaling in the pituitary is required for female but not male fertility","volume":"23","author":"Bliss","year":"2009","journal-title":"Mol Endocrinol"},{"key":"2022031210271280700_B33","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1126\/science.1171396","article-title":"MAPK3\/1 (ERK1\/2) in ovarian granulosa cells are essential for female fertility","volume":"324","author":"Fan","year":"2009","journal-title":"Science"},{"key":"2022031210271280700_B34","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1093\/humrep\/deh609","article-title":"Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries","volume":"20","author":"Rice","year":"2005","journal-title":"Hum Reprod"},{"key":"2022031210271280700_B35","first-page":"2001","article-title":"Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system","volume":"83","author":"Nestler","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031210271280700_B36","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1093\/oxfordjournals.humrep.a138227","article-title":"Insulin actions on ovarian steroidogenesis are not modulated by metformin","volume":"8","author":"Duleba","year":"1993","journal-title":"Hum Reprod"},{"key":"2022031210271280700_B37","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1159\/000292575","article-title":"Insulin stimulates androgen accumulation in incubations of minced porcine theca","volume":"37","author":"Barbieri","year":"1994","journal-title":"Gynecol Obstet Invest"},{"key":"2022031210271280700_B38","first-page":"774","article-title":"Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis","volume":"18","author":"Dunaif","year":"1997","journal-title":"Endocr Rev"},{"key":"2022031210271280700_B39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1210\/edrv-12-1-3","article-title":"On the paradox of insulin-induced hyperandrogenism in insulin-resistant states","volume":"12","author":"Poretsky","year":"1991","journal-title":"Endocr Rev"},{"key":"2022031210271280700_B40","doi-asserted-by":"crossref","first-page":"4742","DOI":"10.1210\/jc.2007-1252","article-title":"Hormonal profile in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus","volume":"92","author":"Codner","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031210271280700_B41","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/0022-4731(88)90344-5","article-title":"Androgen levels during sequential insulin euglycemic clamp studies in patients with polycystic ovary disease","volume":"31","author":"Micic","year":"1988","journal-title":"J Steroid Biochem"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/61\/1\/114\/559627\/114.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/61\/1\/114\/559627\/114.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:27:47Z","timestamp":1667406467000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/61\/1\/114\/15832\/Reproductive-Tissues-Maintain-Insulin-Sensitivity"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,12,12]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2011,12,12]]},"published-print":{"date-parts":[[2012,1,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db11-0956","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,12,12]]}}}