Functional Dichotomy of Developmental Foxp3 + Treg Cell Subsets in the Visceral Adipose Tissue of Lean and Obese Mice

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SUMMARY Chronic inflammation and loss of Foxp3 + regulatory T (Treg) cells in the visceral adipose tissue (VAT) are hallmarks of the pathogenesis of insulin resistance and obesity. This study explores the roles of VAT Treg cells from thymic (tTreg) and peripheral (pTreg) developmental origin, revealing their opposing roles in metabolic inflammation. Obesity destabilized VAT tTreg cells, causing them to clonally expand into obesogenic Foxp3 − IFN-γ + T effector cells, enhancing pro-inflammatory type 1 responses. Genetic tTreg ablation prevented this shift, promoting anti-inflammatory type 2 response, reduced body weight, and improved insulin resistance. Compared to their tTreg counterpart, pTreg cells were functionally well adapted to maintain VAT homeostasis and protect against obesity. Genetic pTreg ablation promoted spontaneous obesity symptoms even with physiological calorie intake, and worsened VAT inflammation and liver steatosis on a high-calorie diet. These findings highlight tTreg instability as a pathogenic threat and pTreg cells as crucial regulators of metabolic homeostasis. Highlights VAT Tregs of lean mice originate from both thymic and peripheral Treg development High-calorie diet destabilizes tTregs that clonally expand into obesogenic IFN-γ + Th1 cells Genetic tTreg deficiency improves steady-state metabolism and prevents diet-induced obesity Genetic pTreg deficiency promotes obesity in both sexes even with normal calorie intake VAT pTregs are particularly adapted to regulate VAT homeostasis, including adipogenesis In Brief Obesity and type 2 diabetes are characterized by insulin resistance, regulatory T (Treg) cell loss, and chronic inflammation in visceral adipose tissue (VAT). In this context, Yilmazer et al. dissect the functional roles of tTreg and pTreg cells. They show that VAT pTreg cells are particularly adapted to exert non-redundant homeostatic functions, and that pTreg deficiency predisposes to obesity even with normal calorie intake. In contrast, VAT tTreg cells can contribute to local inflammation by dedifferentiating into Foxp3 − Th1-polarized effector cells.