Regulatory T (Treg) cells are considered as key regulators of adipose homeostasis and metabolic health. However, the underlying regulatory mechanisms remain unclear. Here we show that expression of G-protein-signaling modulator 1 (GPSM1) in CD4+ T cells in peripheral blood and visceral fat is significantly upregulated in humans upon obesity and glucose dysregulation. Genomic deletion of GPSM1 in CD4+ T cells or Treg cells in mice results in increased numbers of Treg cells in adipose tissues, restrained inflammation and improved insulin and glucose tolerance upon feeding with high fat diet. These metabolic changes are mediated by the maintenance of a specific CD73+CD103+ Treg cell subpopulation. By contrast, mice with CD4+ T-cell-specific overexpression of GPSM1 are characterized by decreased numbers of Treg cells and are more prone to adipose tissue dysfunction and metabolic deterioration. Mechanistically, a RHOA-cell stiffness-TAZ axis mediates the effects of GPSM1 on the abundance of Treg cells. Furthermore, adoptive transfer of GPSM1-deficent Treg cells promotes energy expenditure and improve glucose and lipid metabolism in Rag1 −/− mice. In summary, GSPM1 expression in Treg cells and especially in a subset specialized for metabolic regulation is an important regulator of the overall energy homeostasis. Regulatory T (Treg) cells influence adipose tissue homeostasis and hence metabolic health but the mechanisms are less well known. Here the authors establish, via gain and loss of function mouse models, that GPSM1expression in Treg cells regulate their expansion in adipose tissue, and upon genomic deletion of GSPM1, a specific subset of Treg cells expand and mitigate adipose tissue inflammation caused by high fat diet.
Lyu et al. (2026) studied this question.