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

Regulatory T (T_reg) 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 T_reg cells in mice results in increased numbers of T_reg 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⁺ T_reg cell subpopulation. By contrast, mice with CD4⁺ T-cell-specific overexpression of GPSM1 are characterized by decreased numbers of T_reg 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 T_reg cells. Furthermore, adoptive transfer of GPSM1-deficent T_reg cells promotes energy expenditure and improve glucose and lipid metabolism in Rag1 ^-/- mice. In summary, GSPM1 expression in T_reg cells and especially in a subset specialized for metabolic regulation is an important regulator of the overall energy homeostasis.