title: Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor.
abstract: Obesity is associated with insulin resistance in metabolic tissues such as adipose, liver, and muscle, but it is unclear whether nonclassical target tissues, such as those of the reproductive axis, are also insulin resistant. To determine if the reproductive axis maintains insulin sensitivity in obesity in vivo, murine models of diet-induced obesity (DIO) with and without intact insulin signaling in pituitary gonadotrophs were created. Diet-induced obese wild-type female mice (WT DIO) were infertile and experienced a robust increase in luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) or insulin stimulation. By contrast, both lean and obese mice with a pituitary-specific knockout of the insulin receptor (PitIRKO) exhibited reproductive competency, indicating that insulin signaling in the pituitary is required for the reproductive impairment seen in DIO and that the gonadotroph maintains insulin sensitivity in a setting of peripheral insulin resistance.
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Brothers
authors.forename: Sheng
authors.initials: S
authors.lastname: Wu
authors.forename: Sara A
authors.initials: SA
authors.lastname: DiVall
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Messmer
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Miller
authors.forename: Sally
authors.initials: S
authors.lastname: Radovick
authors.forename: Fredric E
authors.initials: FE
authors.lastname: Wondisford
authors.forename: Andrew
authors.initials: A
authors.lastname: Wolfe
mesh_terms: D000818:Animals; D004032:Diet; D030762:Estrous Cycle / Q000502:physiology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D007247:Infertility, Female / Q000209:etiology* / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications*; D010902:Pituitary Gland / Q000378:metabolism / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D012098:Reproduction / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007328:Insulin; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D011972:Receptor, Insulin
references.citation: Hum Reprod. 2006 May;21(5):1274-8
references.pmid: 16410336
references.citation: Saudi Med J. 2005 Jun;26(6):923-7
references.pmid: 15983675
references.citation: Fertil Steril. 1995 Sep;64(3):634-7
references.pmid: 7641921
references.citation: J Clin Endocrinol Metab. 2003 Nov;88(11):5456-61
references.pmid: 14602789
references.citation: Nature. 2000 Sep 21;407(6802):377-82
references.pmid: 11014193
references.citation: Diabetologia. 1985 Aug;28(8):485-93
references.pmid: 3902539
references.citation: Endocr Rev. 1987 May;8(2):132-41
references.pmid: 3301317
references.citation: Mol Cell Endocrinol. 2009 Nov 13;311(1-2):47-54
references.pmid: 19632296
references.citation: Int J Obes Relat Metab Disord. 2000 May;24(5):639-46
references.pmid: 10849588
references.citation: Fertil Steril. 2003 Oct;80(4):954-65
references.pmid: 14556818
references.citation: Endocrinol Metab Clin North Am. 1999 Jun;28(2):295-324
references.pmid: 10352920
references.citation: Horm Metab Res. 1973 Sep;5(5):333-9
references.pmid: 4148927
references.citation: Nature. 1966 Oct 15;212(5059):289-90
references.pmid: 5970123
references.citation: Growth Horm IGF Res. 1998 Apr;8(2):83-95
references.pmid: 10987675
references.citation: Diabetes. 1985 Apr;34(4):409-12
references.pmid: 3882504
references.citation: Eur J Endocrinol. 1994 Dec;131(6):641-5
references.pmid: 7804448
references.citation: Can J Physiol Pharmacol. 2006 Jul;84(7):725-37
references.pmid: 16998536
references.citation: J Endocrinol. 2006 Feb;188(2):155-65
references.pmid: 16461543
references.citation: Clin Endocrinol (Oxf). 2005 Jul;63(1):73-8
references.pmid: 15963065
references.citation: Biol Reprod. 2009 Sep;81(3):488-96
references.pmid: 19439729
references.citation: Cell. 1999 Feb 5;96(3):329-39
references.pmid: 10025399
references.citation: Annu Rev Physiol. 2006;68:123-58
references.pmid: 16460269
references.citation: Endocrinology. 1991 Mar;128(3):1532-40
references.pmid: 1999171
references.citation: J Clin Endocrinol Metab. 2005 Apr;90(4):2136-41
references.pmid: 15644405
references.citation: J Cell Physiol. 2007 Jul;212(1):105-17
references.pmid: 17311285
references.citation: J Clin Invest. 1976 May;57(5):1320-9
references.pmid: 770505
references.citation: J Endocrinol Invest. 1998 Oct;21(9):602-11
references.pmid: 9856414
references.citation: Eur J Endocrinol. 2001 Jan;144(1):73-9
references.pmid: 11174840
references.citation: Endocrinology. 2004 Mar;145(3):1238-47
references.pmid: 14670988
references.citation: J Mol Endocrinol. 2006 Aug;37(1):63-9
references.pmid: 16901924
references.citation: Rev Endocr Metab Disord. 2004 May;5(2):143-9
references.pmid: 15041790
references.citation: Science. 2000 Sep 22;289(5487):2122-5
references.pmid: 11000114
references.citation: Cell Metab. 2009 Oct;10(4):249-59
references.pmid: 19808018
references.citation: Endocr Rev. 2001 Dec;22(6):818-35
references.pmid: 11739335
references.citation: Growth Horm IGF Res. 2002 Apr;12(2):84-90
references.pmid: 12175645
references.citation: J Clin Endocrinol Metab. 2008 Jun;93(6):2089-96
references.pmid: 18334581
references.citation: Mol Cell Endocrinol. 2006 Apr 25;249(1-2):99-106
references.pmid: 16530935
references.citation: Endocrinology. 2006 Jun;147(6):2754-63
references.pmid: 16513828
references.citation: Endocrinology. 1981 Apr;108(4):1441-9
references.pmid: 6781875
references.citation: Biol Reprod. 1982 Sep;27(2):327-39
references.pmid: 6889895
references.citation: Endocrinology. 2010 Apr;151(4):1863-71
references.pmid: 20176725