Distinct response of adipocyte progenitors to glucocorticoids determines visceral obesity via the TEAD1-miR-27b-PRDM16 axis

Objective

Visceral obesity contributes to obesity-related complications; however, the intrinsic mechanism of depot-specific adipose tissue behavior remains unclear. Despite the pro-adipogenesis role of glucocorticoids (GCs) in adipogenesis, the role of GCs in visceral adiposity rather than in subcutaneous adipose tissue is not established. Because adipocyte progenitors display a striking depot-specific pattern, the regulatory pathways of novel progenitor subtypes within different depots remain unclear. This study describes a cell-specific mechanism underlying visceral adiposity.

Methods

A diverse panel of novel depot-specific adipose progenitors was screened in mice and human samples. The transcriptome distinction and various responses of novel progenitor subtypes of GCs were further measured using the GC receptor-chromatin immunoprecipitation assay and RNA sequencing. The mechanism of novel subtypes was identified using transposase-accessible chromatin analysis and bisulfite sequencing and further confirmed using precise editing of CpG methylation.

Results

Platelet-derived growth factor receptor α (PDGFRα⁺) progenitors, which were dominant in the visceral adipose tissue, were GC-sensitive beige adipose progenitors, whereas CD137⁺ progenitors, which were dominant in the subcutaneous adipose tissue, were GC-passive beige adipose progenitors. Expression of miR-27b, an inhibitor of adipocyte browning, was significantly increased in PDGFRα⁺ progenitors treated with GCs. Using transposase-accessible chromatin analysis, bisulfite sequencing, and precise editing of CpG methylation, TEA domain transcription factor 1 (TEAD1) was discovered to be uniquely hypomethylated in PDGFRα⁺ progenitors.

Conclusions

GCs inhibited the PDGFRα⁺ progenitors' browning process via miR-27b, which was transcriptionally activated by the collaboration of TEAD1 with the GC receptor. These data provide insights into the mechanism of depot-specific variations in high-fat diet-induced obesity.