The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits.

SIM1-expressing paraventricular hypothalamus (PVH) neurons are key regulators of energy balance. Within the PVH population, melanocortin-4 receptor-expressing (PVH) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVH neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVH) neurons, which notably lack MC4Rs, function independently and additively with PVH neurons to account for the totality of PVH neuron-mediated satiety. Moreover, PVH neurons are necessary for prevention of obesity in an independent but equipotent manner to PVH neurons. While PVH and PVH neurons both project to the parabrachial complex (PB), they synaptically engage distinct efferent nodes, the pre-locus coeruleus (pLC), and central lateral parabrachial nucleus (cLPBN), respectively. PB-projecting PVH neurons, like PVH neurons, receive input from interoceptive ARC neurons, respond to caloric state, and are sufficient and necessary to control food intake. This expands the CNS satiety circuitry to include two non-overlapping PVH to hindbrain circuits.