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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281356 | GEO | 2024/11/11

REPOSITORIES: GEO

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Project description:Adipose tissue is found throughout the human body. The diversity of physiological specialization of fat depots is reflected in the depot-specific alterations seen in lipodystrophies and links between specific patterns of fat distribution and susceptibility to diseases, including Type II Diabetes. We compared gene expression patterns in seven anatomically diverse fat depots and in adipocytes and stromal-vascular cells isolated from each sample. Adipocytes from different depots displayed distinct gene expression profiles. Characteristic patterns of expression of HOX genes distinguished adipocyte samples by site of origin. These depot-specific patterns were recapitulated when adipocyte precursors from each site were differentiated ex vivo, suggesting that these genes may have roles in specifying the depot-specific differentiation of adipocytes. Adipocyte expression of 300 genes with roles in energy metabolism showed both depot-dependent and inter-individual variation. Genes involved in glycogen metabolism and de novo fatty acid synthesis were generally most highly expressed in breast and abdominal subcutaneous adipocytes, suggesting a role for these depots in buffering glucose levels. Indeed, the role of adipocytes in primary metabolism of carbohydrate-rich foods may be considerably more important than has been appreciated. Genes involved in lipid uptake and hormone-stimulated lipolysis were on average most highly expressed in pericolonic, omental, and breast adipocytes; their expression covaried with each other and with that of the adipogenic transcription factor PPARG2. Two isoforms of PPARG, PPARG1 and PPARG2, were expressed in distinct patterns, each paralleling a discrete set of putative targets, suggesting that their differential regulation might influence important depot-specific and inter-individual differences in adipocytes. Dozens of genes encoding secreted proteins and receptors were highly expressed in adipocytes compared to adipose stromal-vascular cells and/or other tissues; many of these genes were not previously associated with adipocyte functions and are candidates for novel roles in sensing and signaling energy status to regulate global energy homeostasis.

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

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