α-MSH Stimulates Glucose Uptake in Mouse Muscle and Phosphorylates Rab-GTPase-Activating Protein TBC1D1 Independently of AMPK

Cathrine Laustrup Møller; Rasmus Kjøbsted; Pablo J Enriori; Thomas Elbenhardt Jensen; Cecilia Garcia-Rudaz; Sara A Litwak; Kirsten Raun; Jørgen Wojtaszewski; Birgitte Schjellerup Wulff; Michael A Cowley

doi:10.1371/journal.pone.0157027

α-MSH Stimulates Glucose Uptake in Mouse Muscle and Phosphorylates Rab-GTPase-Activating Protein TBC1D1 Independently of AMPK

PLoS One. 2016 Jul 28;11(7):e0157027. doi: 10.1371/journal.pone.0157027. eCollection 2016.

Affiliations

¹ Steno Diabetes Center, Translational Pathophysiology, 2820 Gentofte, Denmark.
² Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2200 Copenhagen, Denmark.
³ Monash Obesity & Diabetes Institute, Metabolic Neurophysiology Laboratory, Monash University, 3168 Clayton, Australia.
⁴ Department of Pediatrics, Centenary Hospital for Women, Youth and Children and Australian National University, 2605 Canberra, Australia.
⁵ Incretin and Obesity Biology, Novo Nordisk A/S, 2760 Maaloev, Denmark.

Abstract

The melanocortin system includes five G-protein coupled receptors (family A) defined as MC1R-MC5R, which are stimulated by endogenous agonists derived from proopiomelanocortin (POMC). The melanocortin system has been intensely studied for its central actions in body weight and energy expenditure regulation, which are mainly mediated by MC4R. The pituitary gland is the source of various POMC-derived hormones released to the circulation, which raises the possibility that there may be actions of the melanocortins on peripheral energy homeostasis. In this study, we examined the molecular signaling pathway involved in α-MSH-stimulated glucose uptake in differentiated L6 myotubes and mouse muscle explants. In order to examine the involvement of AMPK, we investigate -MSH stimulation in both wild type and AMPK deficient mice. We found that -MSH significantly induces phosphorylation of TBC1 domain (TBC1D) family member 1 (S237 and T596), which is independent of upstream PKA and AMPK. We find no evidence to support that -MSH-stimulated glucose uptake involves TBC1D4 phosphorylation (T642 and S704) or GLUT4 translocation.

MeSH terms

AMP-Activated Protein Kinases / genetics
AMP-Activated Protein Kinases / metabolism*
Animals
GTPase-Activating Proteins / metabolism*
Glucose / metabolism*
Mice
Mice, Knockout
Muscle, Skeletal / drug effects*
Muscle, Skeletal / metabolism
Phosphorylation
Signal Transduction
alpha-MSH / pharmacology*

Substances

GTPase-Activating Proteins
Tbc1d1 protein, mouse
alpha-MSH
AMP-Activated Protein Kinases
Glucose

Grants and funding

The Danish Ministry of Higher Education and Science had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funder Novo Nordisk provided support in the form of salaries for authors [CLM, BSW and KR]. The effect of the melanocortin system on muscle tissue was of interest for Novo Nordisk at the time of the study as an early exploratory research project. The specific roles of these authors are articulated in the ‘author contributions’ section. Veski Australia, National Health and Medical Research Committee (NHMRC) of Australia (GNT 606662), and Pfizer Australia [MAC] had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.