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

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 (PVHGlp1r), melanocortin-4 receptor (PVHMc4r), oxytocin (PVHOxt), and corticotropin-releasing hormone (PVHCrh). We identified both calorie- and state-dependent sustained activity increases and decreases in PVHGlp1r and PVHCrh populations, respectively, while observing transient bulk changes of PVHMc4r, but no response in PVHOxt, neurons to food. Furthermore, we highlight the role of PVHGlp1r neurons in orchestrating acute feeding behavior, independent of the anti-obesity drug liraglutide, and demonstrate the indispensability of PVHGlp1r and PVHMc4r, but not PVHOxt or PVHCrh neurons, in body weight maintenance. •Caloric restoration induces differential activity in the paraventricular hypothalamus•Sensory detection of food rapidly regulates PVHGlp1r and PVHCrh subpopulations•Stimulation of PVHGlp1r neurons bidirectionally orchestrates feeding behavior•Chronic perturbation of PVHGlp1r or PVHMc4r populations induces obesity The hypothalamic paraventricular nucleus has long been implicated in appetite regulation. Li et al. employ a multidisciplinary approach to investigate the physiological response properties of genetically labeled neural populations in this structure to food. They highlight neurons marked by glucagon-like peptide 1 receptor that respond acutely to calories and regulate energy homeostasis.