Orexin and pupillary modulation for hunger control

Fasting-based interventions improve metabolic health and are also explored as adjuncts in other clinical settings, but hunger remains a barrier to adherence. Fasting activates AgRP/NPY neurons (ANs), a hunger-promoting population whose inhibition reduces eating in hungry animals. Here we identify hypocretin/orexin neurons (HONs), classically associated with arousal, as rapid suppressors of AN activity. HON ablation increased AN population activity, whereas HON optostimulation rapidly suppressed it. Combined recordings of AN activity and pupil size-a direct arousal metric not previously linked to AN dynamics-revealed that HONs contributed to pupil dilation-associated AN suppression. In fasted mice, sensory stimulation rapidly recruited this pupil-HON pathway, and suppressed AN activity and eating. These findings reveal an arousal-hunger pathway through which self-initiated pupil dilations, or dilations driven by salient environmental events, interrupt fasting-induced hunger signals. They also suggest a framework for noninvasive, sensory-, and pupillometry-guided approaches to hunger control during fasting.