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

Enriori, Pablo J., Chen, Weiyi, Garcia-Rudaz, Maria C., Grayson, Bernadette E., Evans, Anne E., Comstock, Sarah M., Gebhardt, Ursel, Müller, Hermann L., Reinehr, Thomas, Henry, Belinda A., Brown, Russell D., Bruce, Clinton R., Simonds, Stephanie E., Litwak, Sara A., McGee, Sean L., Luquet, Serge, Martinez, Sarah, Jastroch, Martin, Tschöp, Matthias H., Watt, Matthew J., Clarke, Iain J., Roth, Christian L., Grove, Kevin L. and Cowley, Michael A. 2016, α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors, Molecular metabolism, vol. 5, no. 10, pp. 807-822, doi: 10.1016/j.molmet.2016.07.009.

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Title α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors
Author(s) Enriori, Pablo J.
Chen, Weiyi
Garcia-Rudaz, Maria C.
Grayson, Bernadette E.
Evans, Anne E.
Comstock, Sarah M.
Gebhardt, Ursel
Müller, Hermann L.
Reinehr, Thomas
Henry, Belinda A.
Brown, Russell D.
Bruce, Clinton R.ORCID iD for Bruce, Clinton R. orcid.org/0000-0002-0515-3343
Simonds, Stephanie E.
Litwak, Sara A.
McGee, Sean L.ORCID iD for McGee, Sean L. orcid.org/0000-0001-6953-106X
Luquet, Serge
Martinez, Sarah
Jastroch, Martin
Tschöp, Matthias H.
Watt, Matthew J.
Clarke, Iain J.
Roth, Christian L.
Grove, Kevin L.
Cowley, Michael A.
Journal name Molecular metabolism
Volume number 5
Issue number 10
Start page 807
End page 822
Total pages 16
Publisher Elsevier
Place of publication Amsterdam, The Netherlands
Publication date 2016-10
ISSN 2212-8778
Keyword(s) Glucose homeostasis
MC5R
PKA
Pituitary
Skeletal muscles
α-MSH
Summary 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.
Language eng
DOI 10.1016/j.molmet.2016.07.009
Field of Research 111699 Medical Physiology not elsewhere classified
Socio Economic Objective 920104 Diabetes
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution Non-Commercial No-Derivatives licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30085478

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.