title: Reduced melanocortin production causes sexual dysfunction in male mice with POMC neuronal insulin and leptin insensitivity.
abstract: Proopiomelanocortin (POMC)-derived peptides like α-melanocyte-stimulating hormone (MSH) substantially improve hepatic insulin sensitivity and regulate energy expenditure. Melanocortinergic agents are also powerful inducers of sexual arousal that are being investigated for a possible therapeutic role in erectile dysfunction. It is currently unclear whether reduced melanocortin (MC) activity may contribute to the sexual dysfunction accompanying obesity and type 2 diabetes. Male rodents with leptin and insulin resistance targeted to POMC neurons (leptin receptor [LepR]/insulin receptor [IR]POMC mice) exhibit obesity, hyperinsulinemia, hyperglycemia, and systemic insulin resistance. In this study, we demonstrate that LepR/IRPOMC males are also subfertile due to dramatic alterations in sexual behavior. Remarkably, these reproductive changes are accompanied by decreased α-MSH production not present when a single receptor type is deleted. Unexpectedly, behavioral sensitivity to α-MSH and MC receptor expression are also reduced in LepR/IRPOMC males, a potential adaptation of the MC system to altered α-MSH production. Together, these results suggest that concurrent insulin and leptin resistance in POMC neurons in individuals with obesity or type 2 diabetes can reduce endogenous α-MSH levels and impair sexual function.
authors.affiliation: Department of Physiology and Pharmacology (L.D.F., A.R.D., J.W.H.), College of Medicine, The University of Toledo, Toledo, Ohio 43614-2598; and Division of Endocrinology (R.C.S., E.A.N.), Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island 02912-9107.
authors.forename: Latrice D
authors.initials: LD
authors.lastname: Faulkner
authors.forename: Abigail R
authors.initials: AR
authors.lastname: Dowling
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Stuart
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Nillni
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Hill
mesh_terms: D000374:Aggression / Q000502:physiology; D000818:Animals; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D020738:Leptin / Q000378:metabolism; D008297:Male; D053486:Melanocortins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D012735:Sexual Dysfunction, Physiological / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D020738:Leptin; D053486:Melanocortins; D054411:Receptors, Leptin; D011333:Pro-Opiomelanocortin; D011972:Receptor, Insulin