Human Loss-of-Function ZNRF3 Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion.
Diabetes · ADA · 08/14/2026
Authors: Zhang, Ningning; Lu, Peng; Tong, Yangyi; Cao, Zhiwen; Zhu, Yinmeng; Gong, Yujia; Yin, Nan; Yang, Ruikai; Tong, Muye; Chen, Na; Zhao, Yuxiao; Wu, Chao; Li, Qian; Zhang, Zhongyun; Zhou, Xinyuan; Gu, Dongqin; Liu, Yansong; Cheng, Qianyun; Zhang, Zhiguo; Lu, Jieli
Publication types: Journal Article
PubMed abstract / permitted excerpt
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.
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