Role of regulatory T cells in obesity and insulin resistance

Adipose tissue (AT)-resident regulatory T cells (Tregs) are important regulators of local and systemic inflammation and metabolism. We have previously found that insulin receptor signaling inhibits Treg suppressive function in vitro, and hyperinsulinemia is associated with alterations in visceral AT Tregs in vivo. To directly test the role of Treg-intrinsic insulin receptor signaling, we generated Foxp3(cre)InsR(fl/fl) mice and fed them either chow or high-fat diet (HFD) to induce hyperinsulinemia and obesity. Compared to Foxp3(cre) mice, Foxp3(cre)InsR(fl/fl) mice had improved glucose tolerance and insulin sensitivity after 13 weeks of HFD. This protective metabolic effect was associated with increased brown AT ST2+ Treg numbers and functions and dampened AT inflammation in Foxp3(cre)InsR(fl/fl) mice, rather than changes in food consumption or energy expenditure. Moreover, Foxp3(cre)InsR(fl/fl) mice were protected from age-associated glucose intolerance and insulin resistance as determined in 52-week-old mice. Unlike in the HFD cohort, visceral AT Treg numbers and functions were greatly reduced in aged Foxp3(cre)InsR(fl/fl) mice, leading to increased inflammation in the visceral AT. Surprisingly, elevated AT inflammation was associated with improved metabolic outcomes. Gene expression analysis revealed differential gene signatures in AT Tregs and total AT inflammation, suggesting that the underlying mechanisms contributing to the metabolic syndromes were distinct between the two insulin resistance models. Together, these data suggest that hyperinsulinemia contributes to metabolic syndrome in part by differentially affecting Treg control of AT inflammation in diet-induced versus age-associated metabolic syndrome. In mice, lean visceral AT is populated with anti-inflammatory cells, notably Tregs expressing the IL-33 receptor ST2. Conversely, obese AT contains fewer Tregs and more pro-inflammatory cells. In humans, however, there is limited evidence for a similar pattern of obesity-associated immunomodulation. We used flow cytometry and mRNA quantification to characterize human omental AT in 29 obese individuals, 18 of whom had T2D. Omental AT Treg frequencies negatively correlated to BMI but were comparable between T2D and non-T2D individuals. Compared to human thymic Tregs, omental AT Tregs had a distinct gene signature. ST2, however was not detectable on omental AT Tregs from lean or obese subjects.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat