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

Hunger-promoting AgRP neurons and satiety-promoting POMC neurons in the arcuate nucleus mediate homeostatic regulation of hunger. Yet a rapidly acting satiety component analogous to rapidly hunger-promoting AgRP neurons has been missing. The authors identify this missing satiety signal and show that it is carried by a novel subset of arcuate glutamatergic neurons. 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.