A gain-of-function variant in <i>RICTOR</i> predisposes to human obesity

Mengshan Ni; Yinmeng Zhu; Yufei Chen; Shaoqian Zhao; Aibo Gao; Jieli Lu; Weiqing Wang; Ruixin Liu; Weiqiong Gu; Jie Hong; Jiqiu Wang

doi:10.1016/j.jgg.2025.02.002

Volume 52 Issue 4

Apr. 2025

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Article Navigation > Journal of Genetics and Genomics > 2025 > 52(4): 549-558

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A gain-of-function variant in RICTOR predisposes to human obesity

doi: 10.1016/j.jgg.2025.02.002

a. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
b. Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai 200025, China

Funds:

We thank all participants for their involvement in this study, and Prof. Chi-Chuang Hui from Toronto University for his constructive suggestions. This work was supported by grants from National Key Research and Development Program of China (2022YFC2505201), National Natural Science Foundation of China (92157204, 91957124, and 82250901), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161306, 20171903 Round 2), Innovative Research Team of High-level Local University in Shanghai, and Program of Shanghai Academic Research Leader (20XD1403200, 23XD1422400).

Received Date: 2024-10-25
Accepted Date: 2025-02-09
Rev Recd Date: 2025-02-09

Available Online: 2025-07-11

Publish Date: 2025-02-19

Abstract

Abstract

mTORC1/2 play central roles as signaling hubs of cell growth and metabolism and are therapeutic targets for several diseases. However, the human genetic evidence linking mutations of mTORC1/2 to obesity remains elusive. Using whole-exome sequencing of 1944 cases with severe obesity and 2161 healthy lean controls, we identify a rare RICTOR p.I116V variant enriched in 9 unrelated cases. In Rictor null mouse embryonic fibroblasts, overexpression of the RICTOR p.I116V mutant increases phosphorylation of AKT, a canonical mTORC2 substrate, compared with wild-type RICTOR, indicating a gain-of-function change. Consistent with the human obesity phenotype, the knock-in mice carrying homogenous Rictor p.I116V variants gain more body weight under a high-fat diet. Additionally, the stromal vascular fraction cells derived from inguinal white adipose tissue of knock-in mice display an enhanced capacity for adipocyte differentiation via AKT activity. These findings demonstrate that the rare gain-of-function RICTOR p.I116V mutation activates AKT signaling, promotes adipogenesis, and contributes to obesity in humans.
- RICTOR,
- mTORC2,
- Obesity,
- Gain-of-function,
- AKT,
- Adipogenesis

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