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

Arcuate nucleus (ARC) neurons sense the fed or fasted state and regulate hunger. Agouti-related protein (AgRP) neurons in the ARC (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). Transmission across the ARC^{Glutamatergic}→PVH^MC4R synapse is potentiated by the ARC^POMC neuron-derived MC4R agonist, α-melanocyte stimulating hormone (α-MSH). This excitatory ARC→PVH satiety circuit, and its modulation by α-MSH, provides insight into regulation of hunger and satiety.