α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors

Objective: Central melanocortin pathways are well-established regulators of energy balance. However, scant data exist about the role of systemic melanocortin peptides. We set out to determine if peripheral alpha-melanocyte stimulating hormone (alpha-MSH) plays a role in glucose homeostasis and tested the hypothesis that the pituitary is able to sense a physiological increase in circulating glucose and responds by secreting alpha-MSH. Methods: We established glucose-stimulated alpha-MSH secretion using humans, non-human primates, and mouse models. Continuous alpha-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of alpha-MSH in glucose regulation. Complementary ex vivo and in vitro techniques were employed to delineate the direct action of alpha-MSH via the melanocortin 5 receptor (MC5R) ePKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and alpha-MSH was adopted to restore glucose tolerance in obese mice. Results: Here we demonstrate that pituitary secretion of alpha-MSH is increased by glucose. Peripheral alpha-MSH increases temperature in skeletal muscles, acts directly on soleus and gastrocnemius muscles to significantly increase glucose uptake, and enhances whole-body glucose clearance via the activation of muscle MC5R and protein kinase A. These actions are absent in obese mice, accompanied by a blunting of alpha-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores alpha-MSH induced skeletal muscle glucose uptake and improves glucose disposal in obese mice. Conclusion: These data describe a novel endocrine circuit that modulates glucose homeostasis by pituitary alpha-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity. (C) 2016 The Author(s). Published by Elsevier GmbH.