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Abstract
Adipogenesis, a crucial physiological process, serves to safely sequester lipids, thereby preventing lipotoxicity in peripheral organs and preserving metabolic health during obesity. While insulin signaling plays a pivotal role in adipogenesis, regulating factors, especially the braking mechanism governing this process, warrant further investigation. Our study identified proteasome-dependent degradation of the insulin receptor (IR) during the early stages of adipogenesis as a critical event for the mitotic clonal expansion phase of the adipocyte differentiation program. A series of studies confirmed that the ubiquitinated modification of IR is regulated by E3 ligase FBXO2, and this is based on IR phosphorylation. We further elucidated that the FBD domain of FBXO2 is indispensable for its function in catalyzing p-IR ubiquitination. Gain or loss of function of Fbxo2 inhibited or promoted SVF or 3T3L1 cells proliferation and adipogenesis both in vitro and in vivo, which regulated adipose hyperplasia and plasticity of adipose tissue. Moreover, FBXO2 played an important role in regulating the metabolic health of mice when subjected to caloric excess. Collectively, our findings unveil FBXO2 as a negative regulator of adipogenesis by impairing the insulin signaling pathway.
Acknowledgements
We are grateful for the technical support of the Core Facility Center, Capital Medical University. We thank Dr. Aijuan Qu, Dr. Lin Shan and Dr. Ping Xie from Capital Medical University for their kind help in providing Pdgfrα-Cre mice and experimental support
Funding
This work was supported by the Innovative Group Cultivation Project for Basic Medicine (CX25XT03), Project of Cultivation for young top-notch Talents of Beijing Municipal Institutions (BPHR202203106), Beijing Natural Science Foundation of China (5232002), and Beijing Natural Science Foundation of China (5232003)
Authors and Affiliations
Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Yue Xin, Jiaxin Liu, Zhaoyi Zhai, Haofeng Wu, Muchen Wu, Xueqin Wu, Ruiping Wang, Qi Wang, Xiaowei Jia, Lulu Wang, Tao Lu, Dongliang Fang & Yan Gao
Department of Cardiology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
Yue Xin
Laboratory for Clinical Medicine, Beijing Key Laboratory for Tumor Invasion and Metastasis, Capital Medical University, Beijing, China
Zhaoyi Zhai, Qi Wang, Lulu Wang, Tao Lu & Yan Gao
Department of Experimental Center for Basic Medical Teaching, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Hongwei Shang, Xin Lu, Chun Yang & Yan Gao
Sports Medicine Department, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
Meng Zhou
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Yan Gao
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- Yue XinView author publications
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- Jiaxin LiuView author publications
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- Zhaoyi ZhaiView author publications
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- Haofeng WuView author publications
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The authors declare no competing interests
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All animal experiments were approved by the Medical Ethics Committee of Capital Medical University
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Xin, Y., Liu, J., Zhai, Z. et al. E3 ligase FBXO2-mediated protein stability of insulin receptor regulates adipogenesis and metabolic health in obesity.
Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-09096-z
Received:09 October 2025
Revised:18 June 2026
Accepted:29 June 2026
Published:08 July 2026
DOI
:https://doi.org/10.1038/s41419-026-09096-z
