Adipose tissue cell states linked to progression and clinical subtypes of MASLD in human obesity

Adipose tissue dysfunction is a key determinant of inter-individual variability in obesity-associated comorbidities, yet the underlying tissue-level mechanisms linking adipose remodeling to progression of metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly defined. We applied single-nucleus RNA sequencing to abdominal subcutaneous adipose tissue (SAT) from individuals with severe obesity, stratified by histologically defined MASLD stage, and integrated these data with bulk RNA-seq from ∼200 individuals. MASLD was associated with adipocyte hypertrophy and near-depletion of an ADH1B ^HI adipocyte subset linked to improved lipid buffering and systemic metabolic health. Conversely, lipid-associated macrophages (LAMs) expanded in MASLD, coordinating lipid-handling and inflammatory programs in the myeloid compartment. In advanced metabolic dysfunction-associated steatohepatitis (MASH), we identified a senescence-associated PLAU ^HI progenitor subpopulation with pro-inflammatory signaling potential. Whereas LAMs were broadly enriched in MASLD subtypes, PLAU ^HI progenitors specifically marked a cardiometabolic MASLD endotype, characterized by type 2 diabetes and cardiovascular disease. These findings highlight cellular remodeling of SAT as a driver of MASLD heterogeneity and progression, opening new avenues for targeted therapy.