Abstract P178: The Role of Lateral Hypothalamic Leptin Signaling in Metabolic and Cardiovascular Regulation

Abstract

While neurons in the lateral hypothalamic area (LHA) are clearly involved in feeding, metabolism, and cardiovascular regulation, neurochemically and neuroanatomically heterogeneous nature of LHA neurons has been a challenge in understanding their function in physiological regulation. We have recently identified a unique subset of LHA GABAergic neurons, which are distinct from well-known orexin and MCH neurons, that co-express two metabolically important leptin receptor (LepR) and melanocortin-4 receptor (MC4R), suggesting that these neurons might be the important targets of leptin and melanocortin for metabolic and cardiovascular regulation. Here we show that LHA LepR-positive neurons innervate broadly to intra- and extra-hypothalamic brain regions important for feeding, sympathetic nervous activity, and cardiovascular function, including but not limited to arcuate nucleus, paraventricular nucleus of hypothalamus, parabrachial nucleus, and nucleus of the solitary tract. Stereotaxic microinfusion of leptin into the LHA 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 specific deletion of LepR from LHA significantly increase body weight when fed high-fat diet (44.5 ± 1.9g vs 52.5 ± 2.5g, p<0.01); and selective chemogenetic activation of LHA LepR+ neurons decrease feeding and increase physical activity. Our findings identify the LHA as a novel brain site for leptin to integrate feeding, metabolism and sympathetic regulation. Further investigation of the role of LHA leptin signaling in blood pressure regulation is underway.