Reduced Melanocortin Production Causes Sexual Dysfunction in Male Mice with Pomc Neuronal Insulin and Leptin Insensitivity

Presentation Number: THR-113
Date of Presentation: March 5th, 2015

Latrice Doreen Faulkner*1, Abigail Rebecca Dowling2, Ronald Stuart3, Eduardo A. Nillni3 and Jennifer Wootton Hill4
1Univerisity of Toledo, Toledo, OH, 2The University of Toledo, Toledo, OH, 3The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI, 4University of Toledo School of Medicine, Toledo, OH

Abstract

Pro-opiomelanocortin (POMC)-derived peptides like α-melanocyte-stimulating hormone (α- MSH) are critical regulators of energy expenditure and glucose homeostasis. Melanocortinergic agents are also powerful inducers of sexual arousal and are currently being investigated for a possible therapeutic role in erectile dysfunction in diabetic patients. POMC neuron activity and melanocortin production are regulated by pancreatic insulin and leptin released into the circulation by adipose tissue. In obese states, POMC neurons can become resistant to these factors.  It is currently unclear whether reduced melanocortin activity may contribute to the sexual dysfunction accompanying obesity and type 2 diabetes. In this study, we demonstrate that male rodents with leptin and insulin resistance targeted to POMC neurons (LepR/IRPOMC mice) exhibit obesity, hyperinsulinemia, hyperglycemia, and systemic insulin resistance. This phenotype is also seen with the deletion of the leptin receptor alone. However, our data also indicate that, unlike littermates lacking a single receptor type, LepR/IRPOMC males are subfertile due to dramatic alterations in sexual behavior. Remarkably, these reproductive changes are accompanied by decreased α-MSH production, which is not present when a single receptor type is deleted. Unexpectedly, behavioral sensitivity to α-MSH and melanocortin 4 receptor expression is also reduced in LepR/IRPOMC males, a potential adaptation of the melanocortin system to altered α-MSH production. Together, these results suggest that concurrent insulin and leptin resistance in POMC neurons in individuals with obesity or T2D may reduce endogenous α-MSH levels and impair sexual function.

 

Nothing to Disclose: LDF, ARD, RS, EAN, JWH