2. Academic Validation
  3. Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet-Induced Adiposity

Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet-Induced Adiposity

  • Adv Sci (Weinh). 2023 Apr;10(12):e2207152. doi: 10.1002/advs.202207152.
Yingkai Sun 1 2,  Juan Zhang 1 2,  Jie Hong 1 2,  Zhongyun Zhang 1 2,  Peng Lu 1 2,  Aibo Gao 1 2,  Mengshan Ni 1 2,  Zhiyin Zhang 1 2,  Huanjie Yang 3,  Juan Shen 3,  Jieli Lu 1 2,  Wenzhi Xue 1 2,  Qianqian Lv 1 2,  Yufang Bi 1 2,  Yi Arial Zeng 4,  Weiqiong Gu 1 2,  Guang Ning 1 2,  Weiqing Wang 1 2,  Ruixin Liu 1 2,  Jiqiu Wang 1 2
Affiliations

Affiliations

  • 1 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China.
  • 2 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, P. R. China.
  • 3 BGI Genomics, BGI-Shenzhen, Shenzhen, 860755, P. R. China.
  • 4 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, P. R. China.
PMID: 36755192 DOI: 10.1002/advs.202207152
Abstract

Recent genetic evidence has linked Wnt downstream mutations to fat distribution. However, the roles of WNTs in human obesity remain unclear. Here, the authors screen all Wnt-related paracrine factors in 1994 obese cases and 2161 controls using whole-exome Sequencing (WES) and identify that 12 obese patients harbor the same mutations in RSPO1 (p.R219W/Q) predisposing to human obesity. RSPO1 is predominantly expressed in visceral fat, primarily in the fibroblast cluster, and is increased with adiposity. Mice overexpressing human RSPO1 in adipose tissues develop obesity under a high-fat diet (HFD) due to reduced brown/beige fat thermogenesis. In contrast, Rspo1 ablation resists HFD-induced adiposity by increasing thermogenesis. Mechanistically, RSPO1 overexpression or administration significantly inhibits adipocyte mitochondrial respiration and thermogenesis via LGR4-Wnt/β-catenin signaling pathway. Importantly, humanized knockin mice carrying the hotspot mutation (p.R219W) display suppressed thermogenesis and recapitulate the adiposity feature of obese carriers. The mutation disrupts RSPO1's electrostatic interaction with the extracellular matrix, leading to excessive RSPO1 release that activates LGR4-Wnt/β-catenin signaling and attenuates thermogenic capacity in differentiated beige adipocytes. Therefore, these findings identify that gain-of-function mutations and excessive expression of RSPO1, acting as a paracrine Wnt activator, suppress fat thermogenesis and contribute to obesity in humans.

Keywords

RSPO1; Wnt signaling; obesity; pathogenic gene; thermogenesis; whole-exome sequencing.

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