Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation

Silvana Obici; I. Jack Magrisso; Armen S. Ghazarian; Alireza Shirazian; Jonas R. Miller; Christine M. Loyd; Denovan P. Begg; Kimberly A. Krawczewski Carhuatanta; Michael K. Haas; Jon F. Davis; Stephen C. Woods; Darleen A. Sandoval; Randy J. Seeley; Laurie J. Goodyear; Emmanuel N. Pothos; Joram D. Mul

doi:10.1016/j.molmet.2015.07.003

Molecular Metabolism (Oct 2015)

Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation

Silvana Obici,
I. Jack Magrisso,
Armen S. Ghazarian,
Alireza Shirazian,
Jonas R. Miller,
Christine M. Loyd,
Denovan P. Begg,
Kimberly A. Krawczewski Carhuatanta,
Michael K. Haas,
Jon F. Davis,
Stephen C. Woods,
Darleen A. Sandoval,
Randy J. Seeley,
Laurie J. Goodyear,
Emmanuel N. Pothos,
Joram D. Mul

Affiliations

Silvana Obici: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA
I. Jack Magrisso: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA
Armen S. Ghazarian: Programs in Pharmacology and Experimental Therapeutics and Neuroscience, Sackler School of Graduate Biomedical Sciences and Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA
Alireza Shirazian: Programs in Pharmacology and Experimental Therapeutics and Neuroscience, Sackler School of Graduate Biomedical Sciences and Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA
Jonas R. Miller: Programs in Pharmacology and Experimental Therapeutics and Neuroscience, Sackler School of Graduate Biomedical Sciences and Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA
Christine M. Loyd: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA
Denovan P. Begg: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA
Kimberly A. Krawczewski Carhuatanta: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA
Michael K. Haas: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA
Jon F. Davis: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA
Stephen C. Woods: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA
Darleen A. Sandoval: North Campus Research Complex, Department of Surgery, University of Michigan, Ann Arbor, MI, USA
Randy J. Seeley: North Campus Research Complex, Department of Surgery, University of Michigan, Ann Arbor, MI, USA
Laurie J. Goodyear: Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
Emmanuel N. Pothos: Programs in Pharmacology and Experimental Therapeutics and Neuroscience, Sackler School of Graduate Biomedical Sciences and Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA
Joram D. Mul: Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA

DOI: https://doi.org/10.1016/j.molmet.2015.07.003
Journal volume & issue: Vol. 4, no. 10
pp. 692 – 705

Abstract

Read online

Objective: Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome. Methods: Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4rK314X (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTBMc4r mice, wild-type mice body weight-matched to loxTBMc4r mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats. Results: Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners. Conclusions: Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

About the journal

Abstract

Keywords