Human subcutaneous and visceral adipocyte atlases uncover classical and non-classical adipocytes and depot-specific patterns

Human adipose depots are functionally distinct. Yet, recent single-nucleus RNA-sequencing (snRNA-seq) analyses largely uncovered overlapping/similar cell-type landscapes. We hypothesized that adipocytes subtypes, differentiation trajectories, and/or intercellular communication patterns could illuminate this depot similarity-difference gap. For this, we performed snRNA-seq of human subcutaneous/visceral adipose tissues (5/10 samples, respectively). Of 27,665 adipocyte nuclei in both depots, the majority were “classical”, namely- enriched in lipid metabolism pathways. However, we also observed “non-classical” adipocyte subtypes, enriched in immune-related, extracellular matrix deposition (fibrosis), vascularization/angiogenesis, or ribosomal processes. Pseudo-temporal analysis showed a developmental trajectory from adipose progenitor cells to classical adipocytes via non-classical adipocytes, suggesting that the classical state stems from loss, rather than gain, of specialized functions. Lastly, intercellular communication routes were consistent with the different inflammatory tone of the two depots. Jointly, these findings provide a high-resolution view into the contribution of cellular composition, differentiation, and intercellular communication patterns to human fat depot differences.