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Published on: May 19, 2023
Human Loss-of-Function ZNRF3 Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion
Ningning Zhang1,2, Peng Lu3, Yangyi Tong1,2
1Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Diabetes
|August 14, 2026
Summary
A rare ZNRF3 gene variant linked to obesity impairs fat tissue browning and expansion, affecting glucose levels. This discovery highlights ZNRF3's role in regulating fat distribution and energy expenditure.
Area of Science:
- Genetics
- Metabolism
- Obesity Research
Background:
- The ZNRF3 gene's role in adipose tissue biology was previously unknown.
- A rare ZNRF3 loss-of-function variant (p.V228L) is more common in individuals with obesity.
- This variant is linked to increased subcutaneous white adipose tissue (sWAT) and lower fasting glucose.
Purpose of the Study:
- To investigate the function of ZNRF3 in adipose tissue.
- To understand the impact of the ZNRF3 p.V228L variant on sWAT biology and glucose metabolism.
Main Methods:
- Studied adipocyte-specific Znrf3 knockout mice.
- Generated global ZNRF3 variant knock-in mice.
- Analyzed sWAT browning, expansion, and glucose tolerance in mouse models.
Main Results:
- Impaired sWAT browning and increased sWAT expansion in mice with altered ZNRF3 function.
- Improved glucose tolerance in these mouse models.
- ZNRF3 variant p.V228L is associated with obesity and altered sWAT characteristics.
Conclusions:
- ZNRF3 is a critical genetic regulator of fat distribution and thermogenic capacity.
- Findings provide insights into the precise phenotyping of obesity.
- ZNRF3 influences adipose tissue expansion and energy metabolism.
