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

Madsen, J. D.; Dam, T. V.; Nambiar, J.; Liang, C.; Peltonen, A. R.; Wernberg, C. W.; Rydbirk, R.; Oussoren, L. M. K.; Jakobsen, K. S.; Klinggaard, E. G.; Hansen, D.; Maniyadath, B.; Jonasson, E.; Caterino, T. D.; Krag, A.; Ravnskjaer, K.; Mandrup, S.; Lauridsen, M. E. M.; Loft, A.; Schmidt, S. F.

2025-09-29 cell biology
10.1101/2025.09.25.678284 bioRxiv
Show abstract

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 ADH1BHI 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 PLAUHI progenitor subpopulation with pro-inflammatory signaling potential. Whereas LAMs were broadly enriched in MASLD subtypes, PLAUHI progenitors specifically marked a cardiometabolic MASLD endotype, characterized by type 2 diabetes and cardiovascular disease. These findings highlight cellular remodeling of adipose tissue as a potential driver of MASLD heterogeneity and progression.

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