Unraveling the Neural Networks of Consumption: Novel Central Pathways in Feeding Control and Weight Loss

The regulation of feeding behavior and energy homeostasis involves complex interactions between circadian biology, neurobiology, and metabolic signaling. In these studies, we first provide key insights into the neurocircuitry underlying food entrainment. We developed the first single-nucleus RNA sequencing atlas of the dorsomedial hypothalamus (DMH), identifying DMH-Lepr neurons to play a critical role in orchestrating food anticipatory activity. Next, we investigate the mechanisms by which glucagon-like peptide 1 receptor agonists (GLP1RAs) influence feeding behavior and neuromodulatory networks. By generating novel Glp1r-S33W mouse models expressing humanized GLP1R, we demonstrate that small-molecule and peptide GLP1RAs induce comparable effects in glucose dynamics, feeding, and behavioral patterns. We provide evidence that small-molecule GLP1RAs can directly access blood-brain barrier-impermeable regions such as the central amygdala (CeA), a discovery with significant implications for the treatment of brain-related disorders. Lastly, we identify CeA-Glp1r neurons as key modulators of mesolimbic dopamine release in response to highly palatable foods. These findings provide fundamental insights into the neurobiology of feeding and offer a framework for optimizing next-generation GLP1RA therapies for metabolic and neurological disorders.