Melanocortin receptors mediate renal sympathetic activation to leptin in obesity

Abstract

Leptin acts in the brain to decrease appetite and body weight and increase sympathetic nerve activity (SNA). Obese mice are resistant to the metabolic actions of leptin but have intact renal SNA responses to leptin. The mechanisms that mediate renal SNA response to leptin in obesity remain unknown. We have previously shown the importance of the melanocortin receptors (MCR) in mediating renal SNA response to leptin. Here, we examined the role of MCR in mediating renal sympathoactivation to leptin in obesity by testing the effect of MC3/4R blockade with SHU9119 (30 pM) on the renal SNA response to intracerebroventricular (ICV) leptin in diet‐induced obese (DIO) and agouti obese mice. DIO in C57BL/6J mice was obtained by exposure to 45% high fat diet for 20 weeks. The rise in renal SNA induced by ICV leptin (5 μg) was of the same magnitude in lean (129±10%, n=15), DIO (117±15%, n=8) and agouti obese (115±16%, n=6) mice. ICV pre‐treatment with SHU9119 inhibited (P<0.05) the increase in renal SNA induced by ICV leptin in lean (23±8%, n=10), DIO (9±11%, n=10) and agouti obese (51±14%, n=5) mice. In lean mice, ICV MTII (agonist of MC3/4R, 2 μg) increased renal SNA by 140±41%, n=4) and only 18±9% in presence of SHU9119 (n=5, P=0.003) demonstrating that blockade of renal SNA response by SHU9119 is due to inhibition of MC3/4R. Our data demonstrate the importance of the MCR as key mediators of renal sympathetic activation to leptin in obesity.