Dataset Information

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

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 ?-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.

Methods

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.

Results

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.

Conclusion

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.

SUBMITTER: Enriori PJ

PROVIDER: S-EPMC5034615 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Enriori Pablo J PJ Chen Weiyi W Garcia-Rudaz Maria C MC Grayson Bernadette E BE Evans Anne E AE Comstock Sarah M SM Gebhardt Ursel U Müller Hermann L HL Reinehr Thomas T Henry Belinda A BA Brown Russell D RD Bruce Clinton R CR Simonds Stephanie E SE Litwak Sara A SA McGee Sean L SL Luquet Serge S Martinez Sarah S Jastroch Martin M Tschöp Matthias H MH Watt Matthew J MJ Clarke Iain J IJ Roth Christian L CL Grove Kevin L KL Cowley Michael A MA

Molecular metabolism 20160805 10

<h4>Objective</h4>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.<h4>Methods</h4>We established glucose-stimulated α-MSH secretion us ...[more]

PMID: 27688995

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Project description:Key pointsAlpha-melanocyte stimulating hormone (α-MSH) is an anorexigenic peptide. Injection of the α-MSH analog MTII into the ventral tegmental area (VTA) decreases food and sucrose intake and food reward. Melanocortin-3 receptors (MC3R) are highly expressed in the VTA, suggesting that the effects of intra-VTA α-MSH may be mediated by α-MSH changing the activity of MC3R-expressing VTA neurons. α-MSH increased the firing rate of MC3R VTA neurons in acute brain slices from mice, although it did not affect the firing rate of non-MC3R VTA neurons. The α-MSH induced increase in MC3R neuron firing rate is probably activity-dependent, and was independent of fast synaptic transmission and intracellular Ca2+ levels. These results help us to better understand how α-MSH acts in the VTA to affect feeding and other dopamine-dependent behaviours.AbstractThe mesocorticolimbic dopamine system, the brain's reward system, regulates multiple behaviours, including food intake and food reward. There is substantial evidence that the melanocortin system of the hypothalamus, an important neural circuit controlling feeding and body weight, interacts with the mesocorticolimbic dopamine system to affect feeding, food reward and body weight. For example, melanocortin-3 receptors (MC3Rs) are expressed in the ventral tegmental area (VTA) and our laboratory previously showed that intra-VTA injection of the MC3R agonist, MTII, decreases home-cage food intake and operant responding for sucrose pellets. However, the cellular mechanisms underlying the effects of intra-VTA alpha-melanocyte stimulating hormone (α-MSH) on feeding and food reward are unknown. To determine how α-MSH acts in the VTA to affect feeding, we performed electrophysiological recordings in acute brain slices from mice expressing enhanced yellow fluorescent protein in MC3R neurons to test how α-MSH affects the activity of VTA MC3R neurons. α-MSH significantly increased the firing rate of VTA MC3R neurons without altering the activity of non-MC3R expressing VTA neurons. In addition, the α-MSH-induced increase in MC3R neuron activity was independent of fast synaptic transmission and intracellular Ca2+ levels. Finally, we show that the effect of α-MSH on MC3R neuron firing rate is probably activity-dependent. Overall, these studies provide an important advancement in the understanding of how α-MSH acts in the VTA to affect feeding and food reward.