Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice

Min Yang, Jing Ge, Yu-Lian Liu, Huan-Yu Wang, Zhi-Han Wang, Dan-Pei Li, Rui He, Yu-Yu Xie, Hong-Yan Deng, Xue-Min Peng, Wen-She Wang, Jia-Dai Liu, Zeng-Zhe Zhu, Xue-Feng Yu, Pema Maretich, Shingo Kajimura, Ru-Ping Pan and Yong Chen ()
Additional contact information
Min Yang: Huazhong University of Science and Technology
Jing Ge: Huazhong University of Science and Technology
Yu-Lian Liu: Huazhong University of Science and Technology
Huan-Yu Wang: Huazhong University of Science and Technology
Zhi-Han Wang: Huazhong University of Science and Technology
Dan-Pei Li: Huazhong University of Science and Technology
Rui He: Huazhong University of Science and Technology
Yu-Yu Xie: Huazhong University of Science and Technology
Hong-Yan Deng: Huazhong University of Science and Technology
Xue-Min Peng: Huazhong University of Science and Technology
Wen-She Wang: Huazhong University of Science and Technology
Jia-Dai Liu: Huazhong University of Science and Technology
Zeng-Zhe Zhu: Huazhong University of Science and Technology
Xue-Feng Yu: Huazhong University of Science and Technology
Pema Maretich: Massachusetts Institute of Technology
Shingo Kajimura: Beth Israel Deaconess Medical Center and Harvard Medical School, Howard Hughes Medical Institute
Ru-Ping Pan: Huazhong University of Science and Technology
Yong Chen: Huazhong University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52218-4

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