Duensing, A.; Belmont-Rausch, D.; Tomlinson, A.; Crowley, A.; Sass, F.; Heaton, E.; Coester, B.; Brown, J.; Hassan, S.; Wu, Z.; Qi, N.; Olson, D.; Sabatini, P.; Myers, M.; Pers, T.

While previous studies have suggested that leptin regulates cardiovascular function independently of body weight, the specific leptin receptor (Lepr)-expressing neurons that mediate these distinct effects remain unknown. We found that genes located in blood pressure (BP)-associated genome-wide association study loci were regulated by leptin in Lepr and glucagon-like peptide-1 receptor (Glp1r)-expressing (LeprGlp1r) neurons. Ablating Lepr from these cells decreased BP despite causing hyperphagic obesity. Single-cell and spatial transcriptomics revealed that LeprGlp1r neurons segregate into two distinct subpopulations of cells located in the arcuate nucleus (ARC) and dorsomedial hypothalamic nucleus (DMH). Activating ARC LeprGlp1r neurons suppressed food intake without impacting energy expenditure or cardiovascular function. Conversely, DMH LeprGlp1r neurons increased energy utilization and BP without altering food intake. Our results identify distinct LeprGlp1r neuron subpopulations that dissociate the control of food intake from outputs related to sympathetic tone, including BP, suggesting the potential therapeutic utility of targeting of these subpopulations independently.