Key result
Genetic variants rs73184721 and rs200047724 linked to increased adipocyte size in visceral and subcutaneous fat.
Why the study?
White adipose tissue dysfunction contributes to cardiometabolic disease development, but the cellular microstructure and genetic architecture of adipocyte morphology remain poorly explored.
Meta-Analysis (n=2,667)
Yes
Mean Difference: 930.18
p-value: p=8.82x10^-9
Deep learning-enabled large-scale phenotyping of adipocytes reveals significant genetic loci and confirms associations between adipocyte hypertrophy and cardiometabolic dysfunction.
Adipocyte hypertrophy may mark cardiometabolic risk; leaves open causal role of identified loci and clinical utility.
Background White adipose tissue dysfunction has emerged as a critical factor in cardiometabolic disease development, yet the cellular microstructure and genetic architecture of adipocyte morphology remain poorly explored. Methods We introduce Adipocyte U-Net 2.0, an advanced deep learning method for the semantic segmentation of adipose tissue histology, enabling analysis of over 27 million adipocytes from 2,667 individuals. Findings Our approach revealed that adipocyte hypertrophy associates with metabolic dysfunction, including increased fasting glucose, glycated hemoglobin, leptin, and triglycerides, with decreased adiponectin and HDL cholesterol levels. Through the largest genome-wide association study of adipocyte size to date (N Subcutaneous = 2,066, N Visceral = 1,878), we identified four genome-wide significant loci: two in sex-combined analysis (rs73184721 in NAALADL2 and rs200047724 in NRXN3 ) and two female-specific variants (rs140503338 and rs11656704 in ULK2 ). Notably, these genetic associations showed congruent relationships with cardiometabolic traits, suggesting shared biological mechanisms. Interpretation Our findings demonstrate the utility of deep learning for adipocyte phenotyping at scale and provide novel insights into the genetic basis of adipocyte morphology and its relationship to metabolic disease.
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Jørsboe et al. (2025) conducted a meta-analysis in Adipocyte Hypertrophy / Obesity (n=2,667). Genetic variants (rs73184721 and rs200047724) vs. Reference alleles was evaluated on 95%-quantile of adipocyte size in visceral adipose tissue (rs73184721) (β = 930.18, p=8.82x10^-9). Genetic variants rs73184721 and rs200047724 were significantly associated with increased 95%-quantile adipocyte size in visceral and subcutaneous adipose tissue, respectively.
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