GPSM1 restricts CD73+CD103+ Treg cells in adipose tissue, critical for promoting obesity-related metabolic deterioration

Regulatory T cells (Tregs) have been considered as a key regulator of adipose homeostasis and metabolic health. However, the underlying regulatory mechanisms remain unclear. Here, we report G-protein-signaling modulator 1 (GPSM1) expression in CD4+ T cells of peripheral blood or visceral fat is significantly correlated with human obesity and glucose dysregulation. CD4+ T or Treg cell-specific deletion of GPSM1 mice exhibit increased numbers of Treg in adipose tissues, restrained inflammation and improved insulin and glucose tolerance under a high fat diet. These effects are mediated through maintaining a new CD73+CD103+ Treg subpopulation we identified that mainly accounts for enhanced adipose thermogenesis and suppressive inflammation after GPSM1 deletion, which is revealed by single-nucleus RNA sequencing. By contrast, CD4+ T cell-specific GPSM1 overexpression mice have less numbers of Tregs and are more prone to adipose tissue dysfunction and metabolic deterioration. Mechanistically, RHOA-cell stiffness-TAZ axis mediates the effects of GPSM1 on the abundance of Treg. Furthermore, adoptive transfer of GPSM1-deficent Tregs promotes energy expenditure and improve metabolic performance in Rag1-/- mice, suggesting a therapeutic potential for Treg against obesity and related disorders.