Depletion of fat-resident Treg cells prevents age-associated insulin resistance

Fat-resident regulatory T cells (fTreg cells) accumulate in adipose tissue of mice as a function of age, but not obesity; mice without fTreg cells are protected against age-associated insulin resistance, but remain susceptible to obesity-associated insulin resistance and metabolic disease, indicating different aetiologies of age-associated versus obesity-associated insulin resistance. Age-associated insulin resistance (IR) and obesity-associated IR are physiologically distinct forms of adult-onset diabetes. Although macrophage-driven inflammation drives the obesity-associated condition, the mechanisms for age-associated IR are not known. Ronald Evans and colleagues show that fat-resident regulatory T cells (fTreg cells) accumulate in adipose tissue as a function of age, but not obesity. Mice lacking fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. Depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. Although not the main topic of this study, these findings do not support a role for fTreg cells in obesity-associated insulin resistance or in the therapeutic actions of thiazolidinedione or 'glitazone' antidiabetics. This contradicts claims that Treg cells were beneficial and necessary for restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR1,2,3,4,5,6, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR7 are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fTreg cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fTreg cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR.