Publication Date

12-7-2021

Journal

Cell Reports

DOI

10.1016/j.celrep.2021.110075

PMID

34879284

PMCID

PMC8715676

PubMedCentral® Posted Date

12-29-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Anxiety, Disease Models, Animal, Energy Metabolism, Fasting, Feeding Behavior, Forkhead Transcription Factors, HEK293 Cells, Humans, Hypothalamus, Male, Mice, Knockout, Neurons, Nuclear Receptor Coactivator 2, Obesity, Overnutrition, Pro-Opiomelanocortin, Satiety Response, Signal Transduction, Weight Gain, Mice

Abstract

The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior. SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression. POMC-specific deletion of SRC-2 protects mice from weight gain induced by an obesogenic diet feeding and/or FoxO1 overexpression. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage.

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