Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation.
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.
Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.
Silvana
S
Obici
Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.
I Jack
IJ
Magrisso
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.
Armen S
AS
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
A
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
JR
Miller
Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.
Christine M
CM
Loyd
Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA ; School of Psychology, UNSW Australia, Sydney, NSW, Australia.
Denovan P
DP
Begg
Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.
Kimberly A
KA
Krawczewski Carhuatanta
Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.
Michael K
MK
Haas
Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.
Jon F
JF
Davis
Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA.
Stephen C
SC
Woods
North Campus Research Complex, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
Darleen A
DA
Sandoval
North Campus Research Complex, Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
Randy J
RJ
Seeley
Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
Laurie J
LJ
Goodyear
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.
Emmanuel N
EN
Pothos
Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA ; Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
Joram D
JD
Mul
Diabetes; Dopamine; Food intake; MC4R; Nucleus accumbens; Obesity; Voluntary wheel running