Yilmazer, A.; Eugster, A.; Zevla, D. M.; Helbich, S. S.; Boernert, M.; Torun, B.; Marsela, E.; Kirgin, E.; Dahl, A.; Petzold, A.; Kershaw, O.; Alexaki, V. I.; Chatzigeorgiou, A.; Delacher, M.; Schlenner, S.; Kretschmer, K.

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-{gamma}+ 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.