alpha-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors
AuthorEnriori, PJ; Chen, W; Garcia-Rudaz, MC; Grayson, BE; Evans, AE; Comstock, SM; Gebhardt, U; Mueller, HL; Reinehr, T; Henry, BA; ...
Source TitleMolecular Metabolism
PublisherELSEVIER SCIENCE BV
AffiliationAgriculture and Food Systems
Document TypeJournal Article
CitationsEnriori, P. J., Chen, W., Garcia-Rudaz, M. C., Grayson, B. E., Evans, A. E., Comstock, S. M., Gebhardt, U., Mueller, H. L., Reinehr, T., Henry, B. A., Brown, R. D., Bruce, C. R., Simonds, S. E., Litwak, S. A., McGee, S. L., Luquet, S., Martinez, S., Jastroch, M., Tschoep, M. H. ,... Cowley, M. A. (2016). alpha-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors. MOLECULAR METABOLISM, 5 (10), pp.807-822. https://doi.org/10.1016/j.molmet.2016.07.009.
Access StatusOpen Access
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.
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