Intestinal epithelial cell NCoR deficiency ameliorates obesity and metabolic syndrome
Nuclear receptor corepressor (NCoR1) interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids. An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development. In this study, we found that the deletion of NCoR1 in intestinal epithelial cells (IECs) mainly activated the nuclear receptor PPAR<i>α</i> and attenuated metabolic syndrome by stimulating thermogenesis. The increase in brown adipose tissue thermogenesis was mediated by gut-derived tricarboxylic acid cycle intermediate succinate, whose production was significantly enhanced by PPAR<i>α</i> activation in the fed state. Additionally, NCoR1 deletion derepressed intestinal LXR, increased cholesterol excretion, and impaired duodenal lipid absorption by decreasing bile acid hydrophobicity, thereby reversing the possible negative effects of intestinal PPAR<i>α</i> activation. Therefore, the simultaneous regulatory effect of intestinal NCoR1 on both lipid intake and energy expenditure strongly suggests that it is a promising target for developing metabolic syndrome treatment.
Authors
- Changtao Jiang (ORCID: https://orcid.org/0000-0002-5206-2372)
- Shaocong Hou (ORCID: https://orcid.org/0000-0003-0442-8138)
- Xiaowei Xing (ORCID: https://orcid.org/0009-0000-5480-9591)
- Lijuan Kong (ORCID: https://orcid.org/0009-0005-7194-1443)
- Xingfeng Liu (ORCID: https://orcid.org/0000-0002-7518-5797)
- Qingqing Wu (ORCID: https://orcid.org/0000-0002-7475-5014)
- Andrew M. Johnson (ORCID: https://orcid.org/0000-0002-7269-3016)
- Bing Cui (ORCID: https://orcid.org/0000-0001-8374-7801)
- Caihong Liu (ORCID: https://orcid.org/0000-0002-2557-8090)
- Pingping Li (ORCID: https://orcid.org/0000-0003-0679-270X)
- Qijin Zhao (ORCID: https://orcid.org/0000-0002-1216-1640)
- Qian Jiang (ORCID: https://orcid.org/0000-0002-3969-9141)
- Yibing Chen (ORCID: https://orcid.org/0009-0001-6848-2654)
- Yanjun Wan
- Jingwen Chen (ORCID: https://orcid.org/0009-0001-8717-3929)
- Hengcai Yu
- Peng Zhang (ORCID: https://orcid.org/0009-0004-7146-1805)
Institutions
- Infectious Disease Research Institute (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- National Clinical Research Center for Digestive Diseases (CN)
- Beijing Friendship Hospital (CN)
Publication Details
- Journal
- Acta Pharmaceutica Sinica B
- Published
- 2024-10-11
- DOI
- https://doi.org/10.1016/j.apsb.2024.09.019
- Citations
- 2
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 0.65
Funders
- Beijing Outstanding Young Talents
- National Natural Science Foundation of China
- Chinese Academy of Medical Sciences
- Peking University
- Peking Union Medical College
- Bijzonder Onderzoeksfonds UGent