Obesity is the leading risk factor for metabolic disease, driving pathological adipose tissue (AT) remodeling that disrupts critical endocrine and lipid storage functions. Yet clinical outcomes vary at any given BMI, raising a fundamental question: why do some individuals preserve their health despite high adiposity while others develop complications?
To identify mechanisms underlying metabolic protection, we employed an integrative single-cell genomics approach combining single-nucleus RNA sequencing, spatial transcriptomics, and computational deconvolution across AT depots from metabolically healthy versus unhealthy individuals with obesity. While subcutaneous AT cellular composition remained stable across metabolic phenotypes, visceral AT exhibited extensive disease-associated remodeling characterized by three distinct cellular mechanisms: compromised adipocyte metabolic flexibility, diminished progenitor cell adipogenic capacity, and attenuated mesothelial cell plasticity.
Whereas adipocyte and progenitor cell dysfunction aligned with established AT pathology paradigms, mesothelial cell alterations revealed previously unrecognized complexity. Mesothelial cells, conventionally characterized as quiescent epithelial barriers, demonstrated substantial functional heterogeneity. Our analyses identified multiple mesothelial subpopulations with discrete roles in tissue plasticity. Lineage trajectory analysis integrated with in vitro experiments in primary human cells established that mesothelial plasticity requires reacquisition of stem-cell-like properties, a regenerative program previously documented mainly in wound healing contexts. Spatial transcriptomics localized mesothelial cells not only at visceral AT boundaries but distributed throughout parenchymal tissue, indicating active niche remodeling functions. The loss of mesothelial regenerative capacity strongly correlated with tissue dysfunction and promoted fate conversion toward pro-fibrotic myofibroblast phenotypes. These data position mesothelial cells as context-dependent regulators that either enable adaptive tissue remodeling or propagate pathological fibrosis.
This work establishes the first comprehensive spatial-transcriptional atlas of human AT across metabolic health states in obesity, demonstrating that visceral AT plasticity constitutes a critical determinant of metabolic outcomes. The identification of mesothelial cells as key regulators of tissue homeostasis reveals novel therapeutic avenues for obesity-related metabolic complications.