Intranasal application of the melanocortin 4 receptor agonist MSH/ACTH(4-10) in humans causes lipolysis in white adipose tissue

Objective: The melanocortin system has a highly significant role in the hypothalamic regulation of body weight and energy expenditure. In Animals, intracerebroventricular infusion of Melanocortin Receptor 4 (MCR-4) agonists increases basal metabolic rate through activation of the sympathetic nervous system and subsequently reduces food intake. In humans, direct access of MCR-4 agonists to the central nervous system can be achieved by a transnasal route, which leads to weight loss with chronic administration. In the present study, we aimed at investigating the effects of intranasally administered MC4-R agonist MSH/ACTH(4-10) on lipolysis and sympathetic nervous system activity in healthy humans.

Design: Healthy normal weight, male volunteers (n=10) received either 10 mg MSH/ACTH(4-10) or placebo intranasally in a double-blinded randomized crossover design. Interstitial glycerol release was assessed by microdialysis in abdominal white adipose tissue (WAT) and in skeletal muscle (SM) of the forearm. Local blood flow, systemic blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) within the superficial peroneal nerve were recorded at rest and after nitroprusside infusion.

Results: At 45 min after MSH/ACTH(4-10) administration WAT glycerol concentrations increased by 53.4±19.3% compared with baseline conditions (P<0.05) and remained significantly higher throughout the experiment when compared with placebo (P<0.05) while local glycerol release in SM was not significantly affected. Resting MSNA was not altered by MSH/ACTH(4-10) administration; however, sympathoexcitation by intravenous nitroprusside was markedly elevated (MSH/ACTH(4-10) 569±69% increase to baseline; placebo: 315±64%; P<0.01).

Conclusion: Intranasally administered MCR-4 agonist MSH/ACTH 4-10 increases both subcutaneous WAT lipolysis and MSNA, which suggests a direct central nervous peptide effect in humans on key factors of human energy metabolism.