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

Adipose tissue dysfunction is increasingly recognized as a key determinant of obesity heterogeneity; yet the tissue-level mechanisms that underlie this diversity, and its association with 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 liver histology and integrated these data with bulk RNA-seq from an expanded cohort of >200 individuals. MASLD was characterized by adipocyte hypertrophy and a near-depletion of an ADH1B HI adipocyte subset associated with improved lipid buffering and systemic metabolic health. Conversely, lipid-associated macrophages (LAMs) expanded in MASLD and orchestrated lipid-handling and inflammatory programs in the myeloid compartment. In the advanced form, metabolic dysfunction-associated steatohepatitis (MASH), we identified a senescence-associated PLAU HI progenitor subpopulation with pro-inflammatory signaling potential. While LAMs were broadly associated with MASLD, PLAU HI progenitors were specifically enriched in a cardiometabolic MASLD endotype, characterized by type 2 diabetes and cardiovascular disease. These findings highlight SAT cellular remodeling as a driver of MASLD heterogeneity and progression, pointing to new opportunities for targeted therapy.