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

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

Mol Metab. 2015 Jul 17;4(10):692-705. doi: 10.1016/j.molmet.2015.07.003. eCollection 2015 Oct.

Authors

Silvana Obici¹, I Jack Magrisso¹, Armen S Ghazarian², Alireza Shirazian², Jonas R Miller², Christine M Loyd¹, Denovan P Begg³, Kimberly A Krawczewski Carhuatanta¹, Michael K Haas¹, Jon F Davis¹, Stephen C Woods¹, Darleen A Sandoval⁴, Randy J Seeley⁴, Laurie J Goodyear⁵, Emmanuel N Pothos², Joram D Mul⁶

Affiliations

¹ Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.
² 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.
³ Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA ; School of Psychology, UNSW Australia, Sydney, NSW, Australia.
⁴ North Campus Research Complex, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
⁵ Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
⁶ Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA ; Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.

Abstract

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 Mc4r (K314X) (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB (Mc4r) mice, wild-type mice body weight-matched to loxTB (Mc4r) 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.

Keywords: Diabetes; Dopamine; Food intake; MC4R; Nucleus accumbens; Obesity; Voluntary wheel running.

Grants and funding

P30 DK020572/DK/NIDDK NIH HHS/United States