Brainstem orexigenic neurons drive long-term energy balance via distributed hypothalamic circuits

Energy balance control has long been primarily attributed to hypothalamic neurons, whereas the physiological contribution of brainstem feeding circuits to sustained long-term hyperphagia and weight gain remains poorly defined. Here, we combined viral tracing, optogenetics, chronic chemogenetics, and targeted neuronal ablation to functionally characterize the brainstem neuropeptide Y (NPY) neuronal circuit and define its critical roles in regulating feeding behavior and long-term body weight homeostasis. NPY neurons in the nucleus of solitary tract (NTS^NPY) send parallel, partially overlapping excitatory collaterals to the hypothalamus, each independently driving feeding. Their orexigenic effects persist following the ablation of hypothalamic AgRP/NPY neurons. Chronic NTS^NPY activation induces persistent hyperphagia and weight gain, whereas single or dual ablation of NTS^NPY plus hypothalamic AgRP/NPY failed to disrupt baseline energy homeostasis, revealing redundant brain orexigenic networks. Our data identify NTS^NPY neurons as an extra-hypothalamic pro-obesogenic population independent of canonical AgRP circuits, offering a therapeutic target for obesity.