Obici, SilvanaMagrisso, I. JackGhazarian, Armen S.Shirazian, AlirezaMiller, Jonas R.Loyd, Christine M.Begg, Denovan P.Krawczewski Carhuatanta, Kimberly A.Haas, Michael K.Davis, Jon F.Woods, Stephen C.Sandoval, Darleen A.Seeley, Randy J.Goodyear, LauriePothos, Emmanuel N.Mul, Joram D.2015-11-032015Obici, S., I. J. Magrisso, A. S. Ghazarian, A. Shirazian, J. R. Miller, C. M. Loyd, D. P. Begg, et al. 2015. “Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation☆.” Molecular Metabolism 4 (10): 692-705. doi:10.1016/j.molmet.2015.07.003. http://dx.doi.org/10.1016/j.molmet.2015.07.003.2212-8778http://nrs.harvard.edu/urn-3:HUL.InstRepos:23473902Objective: 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.en-USMC4RNucleus accumbensVoluntary wheel runningDopamineObesityDiabetesFood intakeJournal Article2015-11-0310.1016/j.molmet.2015.07.003