Adipose Tissue Heterogeneity in Cardiometabolic Disease

The global obesity pandemic is worsening in many parts of the world resulting in an increased prevalence of metabolic disease like type 2 diabetes. Despite its strong association with the risk of morbidity, marked interindividual differences in the manifestation of metabolic disease exist, with a subset of obese individuals being classified as metabolically healthy. In detail, these individuals are characterized by retained metabolic health despite excess fat. One of the main factors that predicts metabolic disease risk in obese is the degree of adipose tissue dysfunction. In metabolically healthy obese individuals, adipocytes safely store lipids to maintain systemic health. In contrast, excessive adipocyte expansion drives tissue dysfunction and metabolic disease development. Considering this variability in the metabolic phenotype of obese, one of the main drawbacks in the treatment of obesity is that obese individuals are considered as a uniform population, being defined by a simple and non- informative biometric parameter (BMI > 30). Thus, in this project we aim to elucidate adipocyte-specific factors that drive metabolic disease progression to develop risk-stratified, personalized options for obesity treatment.

Obesity does not carry the same health risk for everyone. A substantial fraction of people with obesity stay free of type 2 diabetes, high blood pressure, and cardiovascular disease, a condition termed metabolically healthy obesity, whereas others develop severe metabolic complications at comparable body weight. Retained function of adipose tissue is one of the strongest predictors of this protection, yet the cellular basis has remained poorly defined, which limits the move toward risk-stratified, personalized obesity care. This project examined human white adipose tissue at single-cell and spatial resolution to identify which cell types and cellular programs separate metabolically healthy from metabolically unhealthy obesity. A comprehensive cellular map of subcutaneous and visceral fat was generated across the metabolic-health spectrum and combined with clinical data, which pinpointed the cell populations whose abundance and activity track most closely with disease. Mesothelial cells, a poorly understood cell type that lines the surface of visceral fat, emerged together with adipocytes and adipocyte progenitors as one of the strongest correlates of metabolic disease. Building on this map, the project established how mesothelial cells contribute to visceral fat remodeling. These cells were shown to undergo a graded identity shift, a mesothelial-to-mesenchymal transition, that can take either a regenerative direction associated with metabolic health or a scar-forming, fibrotic direction associated with metabolic disease. The transcription factor ZEB2 was identified as a central switch governing this decision. Together, the two bodies of work reframe the surface lining of visceral fat as an active participant in metabolic disease and define molecular entry points for distinguishing, and potentially redirecting, harmful from protective fat-tissue remodeling.