Human Loss-of-Function ZNRF3 Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion.
basic_science · Level V
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- Record sourced from PubMed, PMID 42599779.
- Also identified by DOI 10.2337/db25-1108.
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Abstract
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.