Abstract P150: Lateral Hypothalamic Leptin and Melanocortin Signaling in the Regulation of Sympathetic Nerve Activity and Blood Pressure

Abstract

Obesity is associated with increased sympathetic nerve activity (SNA), which contributes to the development of hypertension. Hypothalamus plays a fundamental role in both body weight homeostasis and sympathetic outflow, but the underlying neural basis of this association remains incompletely understood. Leptin and melanocortin systems in the brain are important regulators of body weight homeostasis, SNA and blood pressure. However, the neural circuits by which leptin and melanocortin regulate SNA and blood pressure remain unclear. We have previously shown that both leptin receptor (LepR) and melanocortin 4 receptor (MC4R) are co-expressed in a unique subset of GABAergic neurons in the lateral hypothalamic area (LHA). Because the LHA is a well-known site for SNA and cardiovascular function, we hypothesized that LepR and MC4R signaling in the LHA may play an important role in SNA and blood pressure. Here we show that direct microinfusion of leptin into the LHA increases renal SNA in dose-dependent manner (% changes from baseline at 4 th hour: Vehicle -25.03 ± 7.09 %, 0.05 ug leptin 26.01 ± 9.5 %, 0.5 ug leptin 100.23 ± 26.94 %, n=5-7/group, p<0.001). Additionally, in vivo Cre/loxP system-mediated re-expression of endogenous MC4Rs in the LHA restores the blunted response of MTII-induced increase in renal SNA (Wild-type 66.67 ± 16.53 %, MC4R-null 17.65 ± 10.3 %, MC4R reactivation 48.77 ± 9.36 %, n=7-9/group, p<0.01) and elevates blood pressure in obese, but normotensive MC4R-TB mice in inactive light cycle (Wild-type 111.62 ± 4.07, MC4R-TB 115.75 ± 1.27, MC4R re-expression 125.29 ± 3014 mmHg, n=3-4/group, p<0.05) without significantly affecting body weight. Finally, optogenetic stimulation of LHA LepR-positive neurons decease blood pressure and renal SNA in conscious mice. In conclusion, our findings identify a novel brain circuit by which leptin and melanocortin signaling regulate renal SNA and blood pressure.