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Although genome-wide association studies have implicated ZNRF3 in body fat distribution, the evidence from human genetics and animal models has been lacking. Here, through whole-exome sequencing of 1,944 obese individuals and 2,161 healthy lean control individuals, we identified a rare loss-of-function mutation in human ZNRF3 (p.V228L) observed exclusively in 8 obese individuals. These carriers exhibit increased hip circumference and subcutaneous fat area and lower fasting glucose levels compared with noncarriers. In mice, adipocyte-specific Znrf3 deletion leads to progressive adiposity, with expansion of subcutaneous white adipose tissue (sWAT) and improved glucose tolerance after a long-term high-fat diet. Furthermore, Znrf3 deficiency impairs the browning capacity of sWAT and cold-induced thermogenesis. A knock-in mouse model harboring the homologous human p.V228L mutation recapitulates key features of carriers and knockout mice, including reduced sWAT thermogenic function, altered fat distribution, and improved glucose tolerance. Mechanistically, Znrf3 loss attenuates the cAMP\/cAMP-dependent protein kinase signaling pathway, suppressing UCP1 expression and mitochondrial respiration. Collectively, these findings provide genetic and biological evidence that ZNRF3 regulates thermogenic capacity and remodeling of sWAT, offering new insights into obesity heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>A rare loss-of-function variant in ZNRF3 (p.V228L) is enriched in individuals with obesity and is associated with increased subcutaneous white adipose tissue (sWAT) accumulation and lower fasting glucose levels. Both adipocyte-specific Znrf3 knockout and global variant knock-in impair sWAT browning, increase sWAT expansion, and improve glucose tolerance in mice. These findings establish ZNRF3 as a genetic regulator of fat distribution and thermogenic capacity, informing precise phenotyping of obesity. GWAS has implicated ZNRF3 in human fat distribution, yet its role in adipose tissue biology remains unknown.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-1108","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T16:21:50Z","timestamp":1786724510000},"page":"1794-1809","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Human Loss-of-Function\n                    <i>ZNRF3<\/i>\n                    Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion"],"prefix":"10.2337","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9104-7845","authenticated-orcid":false,"given":"Ningning","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1317-0896","authenticated-orcid":false,"given":"Peng","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University 3 , Jinan, Shandong, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyi","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwen","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinmeng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruikai","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muye","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4829-5915","authenticated-orcid":false,"given":"Yufang","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Geng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shenzhen University of Advanced Technology 4 , Shenzhen, Guangdong, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqiong","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5526-6717","authenticated-orcid":false,"given":"Ruixin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9383-7656","authenticated-orcid":false,"given":"Jiqiu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 1 , Shanghai, P.R. China"},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People\u2019s Republic of China, Shanghai National Center for Translational Medicine 2 , Shanghai, P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"2026092114513788600_B1","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/S2213-8587(20)30110-8","article-title":"Causes, consequences, and treatment of metabolically unhealthy fat distribution","volume":"8","author":"Stefan","year":"2020","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026092114513788600_B2","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/s41574-024-01008-5","article-title":"Metabolically healthy obesity: from epidemiology and mechanisms to clinical implications","volume":"20","author":"Schulze","year":"2024","journal-title":"Nat Rev Endocrinol"},{"key":"2026092114513788600_B3","doi-asserted-by":"crossref","first-page":"bnaa004","DOI":"10.1210\/endrev\/bnaa004","article-title":"Metabolically healthy obesity","volume":"41","author":"Bl\u00fcher","year":"2020","journal-title":"Endocr 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Genet"},{"key":"2026092114513788600_B7","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1038\/s41467-020-15291-z","article-title":"FAM13A affects body fat distribution and adipocyte function","volume":"11","author":"Fathzadeh","year":"2020","journal-title":"Nat Commun"},{"key":"2026092114513788600_B8","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1038\/s41467-020-16592-z","article-title":"RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro","volume":"11","author":"Loh","year":"2020","journal-title":"Nat Commun"},{"key":"2026092114513788600_B9","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nature11019","article-title":"ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner","volume":"485","author":"Hao","year":"2012","journal-title":"Nature"},{"key":"2026092114513788600_B10","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/ng.2953","article-title":"Integrated genomic characterization of adrenocortical carcinoma","volume":"46","author":"Assi\u00e9","year":"2014","journal-title":"Nat Genet"},{"key":"2026092114513788600_B11","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1101\/gad.317412.118","article-title":"A ZNRF3-dependent Wnt\/\u03b2-catenin signaling gradient is required for adrenal homeostasis","volume":"33","author":"Basham","year":"2019","journal-title":"Genes Dev"},{"key":"2026092114513788600_B12","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1016\/j.stem.2021.05.013","article-title":"ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation","volume":"28","author":"Sun","year":"2021","journal-title":"Cell Stem Cell"},{"key":"2026092114513788600_B13","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/s41467-021-27923-z","article-title":"RNF43\/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic 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preadipocytes","volume":"6","author":"Chen","year":"2020","journal-title":"Sci Adv"},{"key":"2026092114513788600_B17","doi-asserted-by":"crossref","first-page":"e2207152","DOI":"10.1002\/advs.202207152","article-title":"Human RSPO1 mutation represses beige adipocyte thermogenesis and contributes to diet-induced adiposity","volume":"10","author":"Sun","year":"2023","journal-title":"Adv Sci (Weinh)"},{"key":"2026092114513788600_B18","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.2337\/dbi20-0015","article-title":"Wnt signaling: from mesenchymal cell fate to lipogenesis and other mature adipocyte functions","volume":"70","author":"Bagchi","year":"2021","journal-title":"Diabetes"},{"key":"2026092114513788600_B19","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/s41580-021-00350-0","article-title":"The cellular and functional complexity of thermogenic fat","volume":"22","author":"Cohen","year":"2021","journal-title":"Nat Rev Mol Cell 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