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.
Graphical Abstract
Included in
Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Medical Sciences Commons
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