Sustained NPY signaling enables AgRP neurons to drive feeding

Abstract

Artificial stimulation of Agouti-Related Peptide (AgRP) neurons promotes intense food consumption, yet paradoxically during natural behavior these cells are inhibited before feeding begins. Previously, to reconcile these observations, we showed that brief stimulation of AgRP neurons can generate hunger that persists for tens of minutes, but the mechanisms underlying this sustained hunger drive remain unknown (Chen et al., 2016). Here we show that Neuropeptide Y (NPY) is uniquely required for the long-lasting effects of AgRP neurons on feeding behavior. We blocked the ability of AgRP neurons to signal through AgRP, NPY, or GABA, and then stimulated these cells using a paradigm that mimics their natural regulation. Deletion of NPY, but not AgRP or GABA, abolished optically-stimulated feeding, and this was rescued by NPY re-expression selectively in AgRP neurons. These findings reveal a unique role for NPY in sustaining hunger in the interval between food discovery and consumption.

NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons

“…Interestingly, a previous study reported that chemogenetic stimulation of AgRP neurons in either NPY-deficient mice or in mice lacking VGAT selectively in AgRP neurons failed to attenuate the rapid feeding response, while the combined deficiency for both VGAT and NPY abrogated the immediate feeding response 10 . In contrast, acute increases in food intake upon optogenetic stimulation of AgRP neurons were dramatically reduced in NPY-deficient mice as revealed in a recent study 11 . Here, we found that deficiency of NPY is sufficient to abrogate virtually completely the immediate feeding and glucose homeostasis regulatory function of AgRP neurons in two complementary models, namely chemogenetic and optogenetic stimulation.…”

“…Previous studies had indicated that the ability of chemogenetic AgRP neuron activation to promote feeding depends on both NPY and GABA release from these cells 10 . A recent study, however, demonstrated that while NPY release is necessary for the ability of optogenetic AgRP neuron activation to fully induce a rapid feeding response, the ability of chemogenetic AgRP neuron activation remained largely unaltered in the absence of NPY 11 . Nevertheless, these studies had not investigated, whether the insulin resistance regulatory role of AgRP neuron activation may depend on functional NPY expression in these neurons.…”

Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat

“…Optogenetic stimulation was perfomed as previously described Chen et al, 2019). A 473 nm laser was passed through a TTL signal generator (H03-14, Following implant surgery, mice were given seven days to recover before experiments.…”

The Pathogenesis of Proventricular Dilatation Disease Caused by Parrot Bornaviruses: A Possible Role For Neuropeptide Y (Npy)

“…A subset of neurons in the arcuate nucleus appear to be critical in regulating appetite. [25] They produce a mediator called agouti-related peptide (AgRP) that promotes food consumption. NPY is required to stimulate their activity in a persistent manner.…”