Melanocortin-responsive Kiss1 neurons of the arcuate nucleus drive energy expenditure through glutamatergic signaling to the dorsomedial hypothalamus.

Energy expenditure (EE) is essential for metabolic homeostasis, yet its central regulation remains poorly understood. Here, we identify arcuate Kiss1 neurons as key regulators of EE in male mice. Ablation of these neurons induced obesity, while their chemogenetic activation increased brown adipose tissue (BAT) thermogenesis without affecting food intake. This action is mediated by glutamatergic projections from Kiss1ARC neurons to CART/Lepr-expressing neurons in the dorsomedial hypothalamus, which activate the raphe pallidus-BAT pathway. CRISPR-mediated deletion of the vesicular glutamate transporter 2 (Vglut2) from Kiss1ARC neurons replicated the obesogenic effect. Furthermore, deletion of the melanocortin 4 receptor (MC4R) from Kiss1 neurons resulted in obesity, reduced energy expenditure and impaired thermogenesis. Optogenetic stimulation of pro-opiomelanocortin (POMC) fibers evoked inward currents in Kiss1 neurons, that were attenuated by MC4R antagonism. Our findings reveal a previously unrecognized neural circuit that mediates melanocortin action on energy expenditure, offering new insights into central mechanisms of metabolic control.