Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced Adiposity
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...
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| Format: | Article |
| Language: | English |
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Wiley
2023-04-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202207152 |
| _version_ | 1797838948302585856 |
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| author | Yingkai Sun Juan Zhang Jie Hong Zhongyun Zhang Peng Lu Aibo Gao Mengshan Ni Zhiyin Zhang Huanjie Yang Juan Shen Jieli Lu Wenzhi Xue Qianqian Lv Yufang Bi Yi Arial Zeng Weiqiong Gu Guang Ning Weiqing Wang Ruixin Liu Jiqiu Wang |
| author_facet | Yingkai Sun Juan Zhang Jie Hong Zhongyun Zhang Peng Lu Aibo Gao Mengshan Ni Zhiyin Zhang Huanjie Yang Juan Shen Jieli Lu Wenzhi Xue Qianqian Lv Yufang Bi Yi Arial Zeng Weiqiong Gu Guang Ning Weiqing Wang Ruixin Liu Jiqiu Wang |
| author_sort | Yingkai Sun |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T15:50:19Z |
| format | Article |
| id | doaj.art-f54f73f7f32647d392b9eac649615610 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-09T15:50:19Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-f54f73f7f32647d392b9eac6496156102023-04-26T12:15:35ZengWileyAdvanced Science2198-38442023-04-011012n/an/a10.1002/advs.202207152Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced AdiposityYingkai Sun0Juan Zhang1Jie Hong2Zhongyun Zhang3Peng Lu4Aibo Gao5Mengshan Ni6Zhiyin Zhang7Huanjie Yang8Juan Shen9Jieli Lu10Wenzhi Xue11Qianqian Lv12Yufang Bi13Yi Arial Zeng14Weiqiong Gu15Guang Ning16Weiqing Wang17Ruixin Liu18Jiqiu Wang19Department 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. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaBGI Genomics BGI‐Shenzhen Shenzhen 860755 P. R. ChinaBGI Genomics BGI‐Shenzhen Shenzhen 860755 P. R. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaState 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. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaDepartment 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. ChinaAbstract 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.https://doi.org/10.1002/advs.202207152obesitypathogenic geneRSPO1thermogenesiswhole‐exome sequencingWnt signaling |
| spellingShingle | Yingkai Sun Juan Zhang Jie Hong Zhongyun Zhang Peng Lu Aibo Gao Mengshan Ni Zhiyin Zhang Huanjie Yang Juan Shen Jieli Lu Wenzhi Xue Qianqian Lv Yufang Bi Yi Arial Zeng Weiqiong Gu Guang Ning Weiqing Wang Ruixin Liu Jiqiu Wang Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced Adiposity Advanced Science obesity pathogenic gene RSPO1 thermogenesis whole‐exome sequencing Wnt signaling |
| title | Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced Adiposity |
| title_full | Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced Adiposity |
| title_fullStr | Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced Adiposity |
| title_full_unstemmed | Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced Adiposity |
| title_short | Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet‐Induced Adiposity |
| title_sort | human rspo1 mutation represses beige adipocyte thermogenesis and contributes to diet induced adiposity |
| topic | obesity pathogenic gene RSPO1 thermogenesis whole‐exome sequencing Wnt signaling |
| url | https://doi.org/10.1002/advs.202207152 |
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