Deep Learning Derived Adipocyte Size Reveals Adipocyte Hypertrophy is under Genetic Control

BackgroundWhite 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. MethodsWe 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. FindingsOur 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 (NSubcutaneous = 2,066, NVisceral = 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. InterpretationOur 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.