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α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors
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 hy...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034615/ https://www.ncbi.nlm.nih.gov/pubmed/27688995 http://dx.doi.org/10.1016/j.molmet.2016.07.009 |
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author | 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. Cowley, Michael A. |
author_facet | 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. Cowley, Michael A. |
author_sort | Enriori, Pablo J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5034615 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-50346152016-09-29 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. Cowley, Michael A. Mol Metab Original Article 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. Elsevier 2016-08-05 /pmc/articles/PMC5034615/ /pubmed/27688995 http://dx.doi.org/10.1016/j.molmet.2016.07.009 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article 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. Cowley, Michael A. α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors |
title | α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors |
title_full | α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors |
title_fullStr | α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors |
title_full_unstemmed | α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors |
title_short | α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors |
title_sort | α-melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034615/ https://www.ncbi.nlm.nih.gov/pubmed/27688995 http://dx.doi.org/10.1016/j.molmet.2016.07.009 |
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