Differential contribution of brain‐region‐specific melanocortin 5 receptor to physical activity levels in lean vs. obesity‐prone rats

Abstract

The brain melanocortin (MC) system consists of peptides such as α‐MSH that act via MC receptors (MCR) to modulate energy balance. MC3R and MC4R are known to alter energy expenditure and food intake, but the role of MC5R in the brain remains poorly understood. We previously demonstrated that high‐activity rats bred for high‐aerobic capacity (HCR) show enhanced MC5R mRNA expression in the peri‐fornical lateral hypothalamus (PeFLH) compared to their low‐activity, low‐aerobic capacity counterparts (LCR). Here, we tested the hypothesis that hypothalamic MC5R expression is integral to the high‐activity phenotype. We measured physical activity (PA) after site‐directed microinjections in the PeFLH, using a specific agonist or antagonist of MC5R in a rat model of leanness vs. obesity (HCR and LCR). Intra‐PeFLH microinjections of the MC5R agonist significantly enhanced PA over a 3‐hour period, and this effect was greater in HCR relative to LCR. Moreoever, the MC5R antagonist significantly suppressed night‐time PA in lean HCR, but not obesity‐prone LCR. The MC5R agonist did not significantly alter food intake in either group. Taken together, these data implicate region‐specific MC5R in individual differences in PA; MC5R‐mediated PA may be a key trait distinguishing the lean phenotype. MC5R agonist was obtained from M. Bednarek (MedImmune Ltd, Cambridge, UK). Research support was from NIH R01NS055859 to CMN and AHA 11PRE7320029 to CS.