Prospective changes in insulin response and cellularity of white adipose tissue following long-term weight loss

Background White adipose tissue (WAT) regulates a plethora of physiological processes, which require the interaction between multiple resident cell types. In insulin resistance/type 2 diabetes, and upon WAT remodeling by weight alterations, the cellular and spatial organization of WAT is drastically altered. However, the cell types governing these changes and their link to insulin sensitivity remain largely unexplored.

Methods Spatial transcriptomics and single nucleus RNA sequencing were employed in subcutaneous WAT from subjects before and five years after weight loss induced by gastric bypass surgery. The response to insulin was determined in vivo at both baseline and follow-up in biopsies obtained before and after hyperinsulinemic-euglycemic clamp. Results were validated by FACS and immunofluorescence.

Results We confirmed the presence of three adipocyte subtypes with distinct transcriptional responses to insulin stimulation. The longitudinal aspect allowed us to study changes in cell heterogeneity following WAT remodeling. Among our unexpected findings, we identified the presence of lipid-associated macrophages (LAMs) in WAT. The proportion of these specialized macrophages was markedly reduced upon weight loss and they displayed a unique response to insulin compared to all other cell types. More specifically, we found that genes encoding macrophage scavenger receptor 1 (MSR1), lysosomal acid lipase/cholesteryl ester hydrolase (LIPA), gamma-aminobutyric acid receptor-associated protein (GABARAP) and Cathepsin S (CTSS) were enriched, suggesting an upregulation of acetylated-LDL uptake and degradation in hyperinsulinemic conditions.

Conclusions Our joint single cell methods allow us to identify novel insulin responding cell targets that, due to their low proportions, cannot be identified using bulk approaches.

Publikationsverlauf

Artikel online veröffentlicht:
02. Mai 2023