Paraventricular Hypothalamic GLP-1R Neurons Mediate Propofol-Induced Suppression of Food Intake

Background: Propofol is a widely used intravenous anesthetic, yet its impact on post-anesthetic feeding remains poorly characterized. The paraventricular nucleus of the hypothalamus (PVN) plays a key role in satiety regulation via glucagon-like peptide-1 receptor (GLP-1R) signaling. This study investigated whether PVNGLP-1R neurons mediate propofol-induced suppression in food intake. Methods: Food intake was measured in wild-type mice following different doses of propofol (25, 50, 100 mg/kg, i.p.) under different conditions (hunger, day and night). The neuronal activation during the period of feeding suppression by anesthesia was assessed via c-Fos immunohistochemistry. In Glp1r-Cre mice, PVNGLP-1R neurons were selectively activated or inhibited using optogenetics to determine their role in post-anesthetic feeding behavior. Fiber photometry with the calcium indicator GCaMP8m was used to record their activity in response to feeding onset during the recovery. Neural circuits were mapped using rabies virus (retrograde tracing) and synaptophysin-based virus (anterograde tracing). Results: An anesthetic dose of propofol (100 mg/kg, i.p.) suppressed food intake, regardless of circadian phase or metabolic state, whereas subanesthetic doses of propofol yielded inconsistent results depending on different scenarios. Propofol anesthesia increased c-Fos expression in PVNGLP-1R neurons. Fiber photometry revealed that propofol abolished the physiological decrease in PVNGLP-1R neuronal activity during food intake. The optogenetic activation of these neurons suppressed food intake, whereas inhibition promoted food intake in the post-anesthetic recovery period. Viral tracing revealed the upstream and downstream targets of PVNGLP-1R neurons and confirmed bidirectional connections between PVNGLP-1R neurons and the key appetite-related nuclei, including the lateral septum (LS), paraventricular thalamus (PVT), arcuate nucleus (ARC) and nucleus tractus solitarius (NTS). Conclusions: PVNGLP-1R neurons are essential mediators of the propofol-induced suppression of food intake.