T reg–specific insulin receptor deletion prevents diet-induced and age-associated metabolic syndrome

Adipose tissue (AT) regulatory T cells (T regs) control inflammation and metabolism. Diet-induced obesity causes hyperinsulinemia and diminishes visceral AT (VAT) T reg number and function, but whether these two phenomena were mechanistically linked was unknown. Using a T reg–specific insulin receptor (Insr) deletion model, we found that diet-induced T reg dysfunction is driven by T reg–intrinsic insulin signaling. Compared with Foxp3(cre) mice, after 13 wk of high-fat diet, Foxp3(cre)Insr(fl/fl) mice exhibited improved glucose tolerance and insulin sensitivity, effects associated with lower AT inflammation and increased numbers of ST2(+) T regs in brown AT, but not VAT. Similarly, Foxp3(cre)Insr(fl/fl) mice were protected from the metabolic effects of aging, but surprisingly had reduced VAT T regs and increased VAT inflammation compared with Foxp3(cre) mice. Thus, in both diet- and aging-associated hyperinsulinemia, excessive Insr signaling in T regs leads to undesirable metabolic outcomes. Ablation of Insr signaling in T regs represents a novel approach to mitigate the detrimental effects of hyperinsulinemia on immunoregulation of metabolic syndrome.