Reduced melanocortin production causes sexual dysfunction in male mice with POMC neuronal insulin and leptin insensitivity.

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.