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A hypothalamic circuit for anticipating future changes in energy balance
Preprint   Open access

A hypothalamic circuit for anticipating future changes in energy balance

Samuel J Walker, Elijah D Lowenstein, Amelia M Douglass, Joseph C Madara, Jon M Resch, Jenkang Tao and Bradford B Lowell
bioRxiv
Cold Spring Harbor Laboratory
09/27/2025
DOI: 10.1101/2025.09.27.678865
PMCID: PMC12485711
PMID: 41040162
url
https://doi.org/10.1101/2025.09.27.678865View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

AgRP neurons cause hunger, the drive to seek and consume food. Their activation by fasting is key for survival and is thought to be triggered by feedback when energy stores are low. However, we know that environmental cues can also regulate AgRP neurons, since cues that predict future food intake rapidly inhibit AgRP neurons. But is the converse true: can the prediction of future fasting rapidly activate AgRP neurons? Here we show that such rapid fasting activation of AgRP neurons does occur. This fasting response is driven by excitatory input from paraventricular hypothalamic neurons expressing , which are bidirectionally sensitive to predictions of future energy state. In this way, cognitively-processed contextual information conveyed by PVH neurons strongly activates AgRP neurons. Lastly, chronic silencing of PVH neurons causes persistent hypophagia. This PVH to AgRP neuron circuit, by anticipating and preventing negative energy balance, provides an important new dimension of hunger regulation.

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