Ningning Zhang, Peng Lu, Yangyi Tong, Zhiwen Cao, Yinmeng Zhu, Yujia Gong, Nan Yin, Ruikai Yang, Muye Tong, Na Chen, Yuxiao Zhao, Chao Wu, Qian Li, Zhongyun Zhang, Xinyuan Zhou, Dongqin Gu, Yansong Liu, Qianyun Cheng, Zhiguo Zhang, Jieli Lu, Yufang Bi, Yong Geng, Weiqing Wang, Guang Ning, Jie Hong, Weiqiong Gu, Ruixin Liu, Jiqiu Wang
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.