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 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.


CONCLUSIONS
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.
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Pablo J
PJ
Enriori
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Weiyi
W
Chen
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Maria C
MC
Garcia-Rudaz
Division Neuroscience, Oregon Health and Science University, Oregon, USA.
Bernadette E
BE
Grayson
Division Neuroscience, Oregon Health and Science University, Oregon, USA.
Anne E
AE
Evans
Division Neuroscience, Oregon Health and Science University, Oregon, USA.
Sarah M
SM
Comstock
Department of Pediatrics, Vestische Children Hospital Datteln, University of Witten/Herdecke, Germany.
Ursel
U
Gebhardt
Department of Pediatrics, Vestische Children Hospital Datteln, University of Witten/Herdecke, Germany.
Hermann L
HL
Müller
Department of Pediatrics, Klinikum Oldenburg GmbH, Germany.
Thomas
T
Reinehr
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Belinda A
BA
Henry
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Russell D
RD
Brown
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Clinton R
CR
Bruce
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Stephanie E
SE
Simonds
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Sara A
SA
Litwak
Metabolic Research Unit, School of Medicine, Deakin University, Vic, Australia.
Sean L
SL
McGee
Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, F-75205 Paris, France.
Serge
S
Luquet
Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, F-75205 Paris, France.
Sarah
S
Martinez
Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg & Division of Metabolic Diseases, Technische Universität, München, Germany.
Martin
M
Jastroch
Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg & Division of Metabolic Diseases, Technische Universität, München, Germany.
Matthias H
MH
Tschöp
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Matthew J
MJ
Watt
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia.
Iain J
IJ
Clarke
Division of Endocrinology, Seattle Children's Hospital Research Institute, WA, USA.
Christian L
CL
Roth
Division Neuroscience, Oregon Health and Science University, Oregon, USA.
Kevin L
KL
Grove
Biomedical Discovery Institute/Department of Physiology, Monash University, Vic, Australia. Electronic address: michael.cowley@monash.edu.
Michael A
MA
Cowley
Glucose homeostasis; MC5R; PKA; Pituitary; Skeletal muscles; α-MSH
J Clin Endocrinol Metab. 1994 Apr;78(4):835-41
8157708
Behav Genet. 2006 Mar;36(2):291-300
16408249
Metabolism. 2009 Jan;58(1):16-21
19059526
J Anat. 1974 Sep;118(Pt 1):155-69
4372205
Mol Cell Endocrinol. 2011 Jul 20;341(1-2):9-17
21616121
Endocrinology. 2003 Dec;144(12):5194-202
12970157
Horm Metab Res. 1990 Feb;22(2):96-100
2157655
J Clin Endocrinol Metab. 2009 Sep;94(9):3535-42
19549745
J Med Chem. 2003 Aug 14;46(17):3728-33
12904077
Diabetes. 2005 Nov;54(11):3198-204
16249445
Clin Endocrinol (Oxf). 2004 Jul;61(1):31-9
15212642
J Med Chem. 2002 Nov 21;45(24):5287-94
12431055
J Endocrinol Invest. 1991 Dec;14(11):919-25
1666898
J Clin Endocrinol Metab. 2005 Feb;90(2):1047-54
15546902
Metabolism. 2010 Feb;59(2):186-94
19766264
FASEB J. 2010 Mar;24(3):862-72
19837866
CNS Drug Rev. 2001 Winter;7(4):387-98
11830756
J Clin Invest. 1990 Nov;86(5):1423-7
2243122
Br J Pharmacol. 2007 Jun;151(4):476-82
17450172
Endocr Res. 2005;31(3):213-8
16392623
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4233-7
11259669
Annu Rev Biochem. 2007;76:481-511
17376027
J Endocrinol. 1986 Nov;111(2):335-42
3025327
Int J Obes (Lond). 2014 Jan;38(1):148-51
23649472
Endocr Rev. 1998 Aug;19(4):477-90
9715376
Diabetes. 2009 Dec;58(12):2757-65
19752162
J Neurosci. 2011 Aug 24;31(34):12189-97
21865462
J Biol Chem. 2003 Apr 11;278(15):12605-8
12538598
Endocr Rev. 2006 Dec;27(7):736-49
17077189
Neurochem Res. 1995 Jan;20(1):107-13
7739752
Int J Obes Relat Metab Disord. 2000 Oct;24(10):1260-4
11093286
Trends Endocrinol Metab. 2000 Oct;11(8):304-8
10996524
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12515-20
21746936
Peptides. 2009 Oct;30(10):1892-900
19646498
Cell. 1997 Dec 12;91(6):789-98
9413988
Shock. 2009 Jun;31(6):553-60
18827746
Pharmacol Rev. 2004 Mar;56(1):1-29
15001661
Eur J Endocrinol. 2003 Aug;149(2):79-90
12887283
Endocrinology. 2000 Sep;141(9):3072-9
10965876
J Clin Invest. 2007 Nov;117(11):3475-88
17885689
J Biol Chem. 2007 Feb 2;282(5):2862-70
17127674
Mol Cell Endocrinol. 2009 May 6;303(1-2):74-81
19428994
Nature. 2007 Sep 13;449(7159):228-32
17728716
Treat Endocrinol. 2006;5(1):7-13
16396514
Diabetes. 2006 Jul;55(7):1923-9
16804059
Endocrinology. 2008 Apr;149(4):2019-26
18162524
J Endocrinol. 1989 Feb;120(2):337-50
2926306
Am J Physiol Endocrinol Metab. 2011 Jul;301(1):E164-71
21505148
J Clin Invest. 2009 Feb;119(2):323-35
19147984
Science. 2005 Oct 28;310(5748):683-5
16254186
Endocrinology. 2004 Jan;145(1):243-52
14551222
Obesity (Silver Spring). 2008 Sep;16(9):2113-9
18551113
Cell Metab. 2007 May;5(5):395-402
17488641
Cell Metab. 2007 Mar;5(3):181-94
17339026
Endocrinology. 1994 Jan;134(1):97-106
8275975
Endocr Pathol. 2006 Summer;17(2):155-64
17159248
Diabetes Metab Rev. 1996 Apr;12(1):15-36
8861499
J Clin Endocrinol Metab. 2012 Sep;97(9):E1720-5
22723325
J Clin Invest. 2001 Oct;108(7):1079-85
11581309
Endocrinology. 2013 Apr;154(4):1444-53
23471217