Abstract P1118: The Role of Lateral Hypothalamic Leptin Circuitry in Autonomic Control of Cardiovascular Function

Abstract

Obesity is commonly associated with sympathetic overactivity and elevated blood pressure, and accumulating evidence suggests that an adipocyte-derived metabolic hormone, leptin, may plays an important role in these pathological processes, likely through a mechanism of so-called ‘selective leptin resistance’. However, underlying neural circuits through which leptin causes sympathoexcitation and increases blood pressure remain incompletely understood. Here we hypothesized that leptin may acts on a subset of lateral hypothalamic area (LHA) neurons to affect cardiovascular functions. We show that stereotaxic microinfusion of leptin into the LHA dose-dependently increases renal sympathetic nerve activity (RSNA) (% changes from baseline at 4 th hour: vehicle -25.03 ± 7.09 % vs leptin 100.23 ± 26.94 %, p<0.001) and selective chemogenetic activation of LHA LepR-expressing neurons increase arterial pressure compared to control mice (19.43 ± 0.87 mm of Hg, p<0.05). Consistent with these functional observations, viral-mediated cell type-specific anterograde tracing revealed that LHA LepR-expressing neurons, which are distinct from well-known orexin and MCH neurons, broadly innervate brain regions known for autonomic regulation, including but not limited to paraventricular nucleus, nucleus of solitary tractus, locus coeruleus, and ventrolateral medulla. These findings identify the LHA as a novel brain site critical for leptin to regulate RSNA and arterial pressure.