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.
Highlights
Agouti-Related Peptide (AgRP) neurons are a small population of cells in the arcuate nucleus of the hypothalamus that are critical for regulating food intake (Andermann and Lowell, 2017)
We found that control mice, as well as mice lacking GABA or AgRP, showed a clear dose-response relationship between pre-stimulation duration and total food intake (Figure 1E,F and Figure 1—figure supplement 1)
Consistent with this, Neuropeptide Y (NPY) is highly expressed in hungerpromoting AgRP neurons (Hahn et al, 1998), and its expression in these cells is increased by energy deficit (Sahu et al, 1988; White and Kershaw, 1990)
Summary
AgRP neurons are a small population of cells in the arcuate nucleus of the hypothalamus that are critical for regulating food intake (Andermann and Lowell, 2017). AgRP neurons are gradually activated during fasting, they are inhibited within seconds when a hungry animal sees or smells food (Betley et al, 2015; Chen et al, 2015; MandelblatCerf et al, 2015) This rapid inhibition of AgRP neurons often occurs before a single bite of food has been consumed and persists for the duration of the ensuing meal. Consistent with this, we showed that brief optogenetic stimulation of AgRP neurons in the absence of food can drive voracious food intake tens of minutes later, long after AgRP neuron stimulation has been terminated (Chen et al, 2016) This indicates that AgRP neurons can generate an unusual ‘sustained hunger drive’ that outlasts their acute firing (Figure 1A). The mechanisms underlying this long-lasting potentiation of feeding behavior are unknown
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