A rapidly-acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH

Arcuate nucleus (ARC) neurons sense the fed/fasted state and regulate hunger. Agouti-related protein (ARC(AgRP)) neurons are stimulated by fasting, and once activated, they rapidly (within minutes) drive hunger. Pro-opiomelanocortin (ARC(POMC)) neurons are viewed as the counterpoint to ARC(AgRP) neurons. They are regulated in an opposite fashion and decrease hunger. However, unlike ARC(AgRP) neurons, ARC(POMC) neurons are extremely slow in affecting hunger (many hours). Thus, a temporally analogous, rapid ARC satiety pathway does not exist or is presently unidentified. Here, we show that glutamate-releasing ARC neurons expressing oxytocin receptor, unlike ARC(POMC) neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARC(AgRP) projections on melanocortin-4 receptor (MC4R)-expressing satiety neurons in the paraventricular hypothalamus (PVH(MC4R) neurons). Importantly, transmission across the ARC(Glutamatergic)→PVH(MC4R) synapse is potentiated by the ARC(POMC) neuron-derived MC4R agonist, α-MSH. This excitatory ARC→PVH satiety circuit, and its modulation by α-MSH, provides new insight into regulation of hunger/satiety.