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^SIM1 population, melanocortin-4 receptor-expressing (PVH^MC4R) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVH^SIM1 neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVH^PDYN) neurons, which notably lack MC4Rs, function independently and additively with PVH^MC4R neurons to account for the totality of PVH^SIM1 neuron-mediated satiety. Moreover, PVH^PDYN neurons are necessary for prevention of obesity in an independent but equipotent manner to PVH^MC4R neurons. While PVH^PDYN and PVH^MC4R 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^PDYN neurons, like PVH^MC4R neurons, receive input from interoceptive ARC^AgRP 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.