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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. Jr.* ; Bruce, C.R.* ; Simonds, S.E.* ; Litwak, S.A.* ; McGee, S.L.* ; Luquet, S.* ; Martinez, S.* ; Jastroch, M. ; Tschöp, M.H. ; Watt, M.J.* ; Clarke, I.J.* ; Roth, C.L.* ; Grove, K.L.* ; Cowley, M.A.*

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

Mol. Metab. 5, 807-822 (2016)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Glucose Homeostasis ; Mc5r ; Pka ; Pituitary ; Skeletal Muscles ; α-msh; High-fat Diet; Skeletal-muscle; Insulin-resistance; Human Pituitary; Beta-endorphin; Plasma-levels; Diabetes-mellitus; Leptin Resistance; Obese Men; Metabolism
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Zeitschrift Molecular Metabolism
Quellenangaben Band: 5, Heft: 10, Seiten: 807-822 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)