Hypothalamic steroid receptor coactivator-2 regulates adaptations to fasting and overnutrition

Authors: YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); HE, YANLIN - Pennington Biomedical Research Center; LIU, HAILAN - Children'S Nutrition Research Center (CNRC); ZHOU, WENJUN - Baylor College Of Medicine; WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); XU, PINGWEN - University Of Illinois; CAI, XING - Chinese Academy Of Sciences; LIU, HESONG - Children'S Nutrition Research Center (CNRC); YU, KAIFAN - Children'S Nutrition Research Center (CNRC); PEI, ZHOU - Children'S Nutrition Research Center (CNRC); HYSENI, ILIRJANA - Children'S Nutrition Research Center (CNRC); FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC); TONG, QINGCHUN - University Of Texas Health Science Center; XU, JIANMING - Baylor College Of Medicine; SUN, ZHENG - Baylor College Of Medicine; O'MALLEY, BERT - Baylor College Of Medicine; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/9/2021
Publication Date: 12/7/2021
Citation: Yang, Y., He, Y., Liu, H., Zhou, W., Wang, C., Xu, P., Cai, X., Liu, H., Yu, K., Pei, Z., Hyseni, I., Fukuda, M., Tong, Q., Xu, J., Sun, Z., O'Malley, B., Xu, Y. 2021. Hypothalamic steroid receptor coactivator-2 regulates adaptations to fasting and overnutrition. Cell Reports. 37. Article 110075. https://doi.org/10.1016/j.celrep.2021.110075.
DOI: https://doi.org/10.1016/j.celrep.2021.110075

Interpretive Summary: When food supplies are low or during fasting, organisms can reduce their energy expenditure to function and survive. In this study, we investigate how these adaptations relate to a receptor protein called steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons in the hypothalamus. We found that SRC-2 is required to retain the ability to reduce energy expenditure and to maintain glucose levels that allow the animal to survive. When an animal living in the wild has not eaten in a while, it needs to venture into its environment to search for food, but the resulting exposure to predators creates anxiety. We found that SRC-2 helps overcome the anxiety triggered by the need to go out to feed, facilitating the search for food. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage.

Technical 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 excit-ability 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.