Elsevier

Molecular Metabolism

Volume 5, Issue 10, October 2016, Pages 807-822
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2016.07.009Get rights and content
Under a Creative Commons license
open access

Highlights

  • Glucose stimulates α-MSH release from the pituitary.

  • Systemic α-MSH drives glucose disposal and thermogenesis in skeletal muscles.

  • α-MSH acts on MC5R expressed on skeletal muscles and activate cAMP-PKA pathway.

  • The combined treatment of nonselective or selective PDE 4 inhibitor and α-MSH ameliorates glucose intolerance in obese mice.

Abstract

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 α-melanocyte stimulating hormone (α-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 α-MSH.

Methods

We established glucose-stimulated α-MSH secretion using humans, non-human primates, and mouse models. Continuous α-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of α-MSH in glucose regulation. Complementary ex vivo and in vitro techniques were employed to delineate the direct action of α-MSH via the melanocortin 5 receptor (MC5R)–PKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and α-MSH was adopted to restore glucose tolerance in obese mice.

Results

Here we demonstrate that pituitary secretion of α-MSH is increased by glucose. Peripheral α-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 α-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores α-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 α-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity.

Keywords

α-MSH
Pituitary
Skeletal muscles
MC5R
PKA
Glucose homeostasis

Cited by (0)

9

Present address: Department of Paediatric, Division of Women, Youth and Children, The Canberra Hospital, ACT, Australia.

10

Present address: University of Mississippi Medical Center, MI, USA.

11

Pablo J. Enriori and Weiyi Chen contributed equally to this work.