Defined Paraventricular Hypothalamic Populations Exhibit Differential Responses to Food Contingent on Caloric State

Summary Understanding the neural framework behind appetite control is fundamental to developing effective therapies to combat the obesity epidemic. The paraventricular hypothalamus (PVH) is critical for appetite regulation, yet, the real-time, physiological response properties of PVH neurons to nutrients are unknown. Using a combination of fiber photometry, electrophysiology, immunohistochemistry, and neural manipulation strategies, we determined the population dynamics of four molecularly delineated PVH subsets implicated in feeding behavior: glucagon-like peptide 1 receptor (PVH Glp1r ), melanocortin-4 receptor (PVH Mc4r ), oxytocin (PVH Oxt ), and corticotropin-releasing hormone (PVH Crh ). We identified both calorie- and state-dependent sustained activity increases and decreases in PVH Glp1r and PVH Crh populations, respectively, while observing transient bulk changes of PVH Mc4r , but no response in PVH Oxt , neurons to food. Furthermore, we highlight the role of PVH Glp1r neurons in orchestrating acute feeding behavior, independent of the anti-obesity drug liraglutide, and demonstrate the indispensability of PVH Glp1r and PVH Mc4r , but not PVH Oxt or PVH Crh neurons, in body weight maintenance.