Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice
Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation and facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation. Depletion of sortilin in adipocytes results in an increase of mitochondrial ACSL1 and the activation of AMPK/PGC1α signaling, thereby activating beige fat and preventing high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings indicate that sortilin controls adipose tissue fatty acid oxidation by substrate fuel selection during beige fat activation and provides a potential targeted approach for the treatment of metabolic diseases.
Authors
- Danpei Li (ORCID: https://orcid.org/0000-0003-4972-976X)
- Yuyu Xie
- Xuefeng Yu (ORCID: https://orcid.org/0000-0003-3961-9321)
- Huan‐Yu Wang (ORCID: https://orcid.org/0000-0001-5650-7466)
- Rui He (ORCID: https://orcid.org/0000-0002-2368-7269)
- Xuemin Peng
- Zengzhe Zhu
- Shingo Kajimura (ORCID: https://orcid.org/0000-0003-0672-5910)
- Pema Maretich (ORCID: https://orcid.org/0000-0001-5058-812X)
- Min Yang (ORCID: https://orcid.org/0000-0003-2924-5717)
- Yulian Liu (ORCID: https://orcid.org/0000-0003-1520-034X)
- Yong Chen (ORCID: https://orcid.org/0000-0002-3634-0328)
- Jiadai Liu (ORCID: https://orcid.org/0000-0002-4032-0856)
- Zhihan Wang (ORCID: https://orcid.org/0000-0002-3617-477X)
- Hongyan Deng (ORCID: https://orcid.org/0009-0001-9903-5347)
- Jing Ge (ORCID: https://orcid.org/0009-0009-3664-7811)
- Ruping Pan
- Wen-She Wang
Institutions
- Beth Israel Deaconess Medical Center (US)
- National Clinical Research Center for Digestive Diseases (CN)
- National Clinical Research (US)
- Tongji Hospital (CN)
- Huazhong University of Science and Technology (CN)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-04
- DOI
- https://doi.org/10.1038/s41467-024-52218-4
- Citations
- 16
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 5.22
Funders
- National Natural Science Foundation of China
- Tongji University