IL-1β engages distinct peripheral sensory circuits to suppress feeding across time.

Loss of appetite is a hallmark of acute and chronic inflammation, and sustained anorexia causes malnutrition and worsens disease outcomes. Interleukin-1β (IL-1β) is one of the most potently anorexigenic inflammatory cytokines, yet how it engages neural circuits that suppress feeding remains incompletely understood. Specifically, the role of peripheral sensory neurons in mediating IL-1β-induced anorexia is unresolved. Here, using DREADD-mediated inhibition of discrete peripheral sensory neuron populations and fiber photometry, we show that IL-1β-induced anorexia occurs in at least two temporally and mechanistically distinct phases. Shortly after IL-1β administration, prostaglandin signaling through non-vagal sensory afferents rapidly inhibits hypothalamic AgRP neurons to suppress food intake. At later time points, anorexia becomes partially prostaglandin-independent and vagal afferent neuron-dependent. Our findings demonstrate that multiple molecular signals mediate IL-1β-induced anorexia, and that diverse peripheral sensory pathways, including a previously unappreciated contribution from non-vagal afferents, are critical links between systemic inflammation and neural control of appetite.