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

Pablo J. Enriori, Weiyi Chen, Maria C. Garcia-Rudaz, Bernadette E. Grayson, Anne E. Evans, Sarah M. Comstock, Ursel Gebhardt, Hermann L. Müller, Thomas Reinehr, Belinda A. Henry, Russell D. Brown, Clinton R. Bruce, Stephanie E. Simonds, Sara A. Litwak, Sean L. McGee, Serge Luquet, Sarah Martinez, Martin Jastroch, Matthias H. Tschöp, Matthew J. WattIain J. Clarke, Christian L. Roth, Kevin L. Grove, Michael A. Cowley

    Research output: Contribution to journalArticle

    20 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)807-822
    Number of pages16
    JournalMolecular Metabolism
    Volume5
    Issue number10
    DOIs
    StatePublished - Oct 1 2016

    Keywords

    • Glucose homeostasis
    • MC5R
    • PKA
    • Pituitary
    • Skeletal muscles
    • α-MSH

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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  • Cite this

    Enriori, P. J., Chen, W., Garcia-Rudaz, M. C., Grayson, B. E., Evans, A. E., Comstock, S. M., Gebhardt, U., Müller, 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., Tschöp, M. H., ... Cowley, M. A. (2016). α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors. Molecular Metabolism, 5(10), 807-822. https://doi.org/10.1016/j.molmet.2016.07.009