UBC Theses and Dissertations
Function and control of adipose tissue regulatory T cells : implications for obesity Han, Jonathan Martin
Obesity is associated with chronic low-grade inflammation in visceral adipose tissue (VAT), which promotes the development of insulin resistance. The role of adaptive immunity in VAT inflammation has only recently been investigated. Initial studies suggest that VAT-resident regulatory T cells (Tregs) have a prominent role in suppressing VAT inflammation and correcting metabolic dysfunction in obese mice. I sought to investigate how Tregs in the VAT are regulated. Obesity is accompanied by a rise in insulin levels, and whether this hyperinsulinemia affects the progression of inflammation is not known. I first found that Tregs express the insulin receptor, and high levels of insulin inhibited IL-10 production and the ability of Tregs to suppress macrophages. In parallel, Tregs from the VAT of obese mice showed a similar decrease in IL-10 production, suggesting that hyperinsulinemia may contribute to the development of obesity-associated inflammation via an effect of insulin on Treg function. I then found that the majority of IL-10-expressing Tregs in the VAT expressed the ST2 chain of the IL-33 receptor. The proportion of ST2+ Tregs in VAT was severely diminished in obese mice, and this effect could be completely reversed by treatment with IL-33. IL-33 treatment also reversed VAT inflammation in obese mice, and resulted in a reduction of hyperinsulinemia and insulin resistance. These data suggested that IL-33 is critical for the maintenance of ST2+ Tregs in the VAT, and that delivery of IL-33 may be a new therapeutic approach to reverse obesity-associated Treg deficiency, inflammation and insulin resistance. It is not known whether Tregs and adipocytes can directly interact in the VAT. I found that soluble factors produced by adipocytes significantly increased survival and IL-10 production from Tregs, and caused a shift towards oxidative metabolism in vitro. Similarly, Tregs resident in mouse VAT have substantially increased expression of IL-10 compared to those found in the periphery, indicating that the interaction between Tregs and adipocytes may contribute to the functional specialization of Tregs in the VAT. Taken together, these data suggest that insulin, IL-33 and adipocyte-produced factors regulate IL-10-expressing Tregs and their ability to control inflammation in the VAT.
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