Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic

Leptin plays an important role in regulation of body weight through regulat ion of food intake and sympathetically mediated thermogenesis. The hypothal amic melanocortin system, via activation of the melanocortin-4 receptor (MC 4-R), decreases appetite and weight, but its effects on sympathetic nerve a ctivity (SNA) are unknown. In addition, it is not known whether sympathoact ivation to leptin is mediated by the melanocortin system. We tested the int eractions between these systems in regulation of brown adipose tissue (BAT) and renal and lumbar SNA in anesthetized Sprague-Dawley rats. Intracerebro ventricular administration of the MC4-R agonist MT-II (200 to 600 pmol) pro duced a dose-dependent sympathoexcitation affecting BAT and renal and lumba r beds. This response was completely blocked by the MC4-R antagonist SHU911 9 (30 pmol ICV), Administration of leptin (1000 mu g/kg IV) slowly increase d BAT SNA (baseline, 41+/-6 spikes/s; 6 hours, 196+/-28 spikes/s; P=0.001) and renal SNA (baseline, 116+/-16 spikes/s; 6 hours, 169+/-26 spikes/s; P=0 .014). Intracerebroventricular administration of SHU9119 did not inhibit le ptin-induced BAT sympathoexcitation (baseline, 35+/-7 spikes/s; 6 hours, 15 8+/-34 spikes/s; P=0.71 versus leptin alone). However, renal sympathoexcita tion to leptin was completely blocked by SHU9119 (baseline, 142+/-17 spikes /s; 6 hours, 146+/-25 spikes/s; P=0.007 versus leptin alone). This study de monstrates that the hypothalamic melanocortin system can act to increase sy mpathetic nerve traffic to thermogenic BAT and other tissues. Our data also suggest that leptin increases renal SNA through activation of hypothalamic melanocortin receptors. In contrast, sympathoactivation to thermogenic BAT by leptin appears to be independent of the melanocortin system.