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

Abstract

AbstractObjectiveVisceral 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.MethodsA 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.ResultsPlatelet‐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.ConclusionsGCs 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.