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 ?-melanocyte stimulating hormone (?-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 ?-MSH.We established glucose-stimulated ?-MSH secretion using humans, non-human primates, and mouse models. Continuous ?-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of ?-MSH in glucose regulation. Complementary ex vivo and in vitro techniques were employed to delineate the direct action of ?-MSH via the melanocortin 5 receptor (MC5R)-PKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and ?-MSH was adopted to restore glucose tolerance in obese mice.Here we demonstrate that pituitary secretion of ?-MSH is increased by glucose. Peripheral ?-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 ?-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores ?-MSH induced skeletal muscle glucose uptake and improves glucose disposal in obese mice.These data describe a novel endocrine circuit that modulates glucose homeostasis by pituitary ?-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity.     «

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 ?-melanocyte stimulating hormone (?-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 ?-MSH.We established glucose-stimulated ?-MSH secretion using humans, non-human primates, an...     »