IL-33 Reverses an Obesity-Induced Deficit in Visceral Adipose Tissue ST2+ T Regulatory Cells and Ameliorates Adipose Tissue Inflammation and Insulin Resistance

Abstract

Obesity is associated with insulin resistance and inflammation thought to be caused by a visceral adipose tissue (VAT)–localized reduction in immunoregulatory cells and increase in proinflammatory immune cells. We previously found that VAT regulatory T cells (Tregs) normally express high levels of IL-10 and that expression of this cytokine in VAT Tregs is specifically reduced in mice fed a high-fat diet. In this study, we further investigated the phenotype of VAT Tregs and found that the majority of IL-10–expressing Tregs in the VAT of lean mice also expressed the ST2 chain of the IL-33R. In addition to high expression of IL-10, ST2+ Tregs in lean VAT expressed higher proportions of Th2-associated proteins, including GATA3 and CCR4, and Neuropillin-1 compared with ST2− Tregs. The proportion of ST2+ Tregs in VAT was severely diminished in obese mice that had been fed a high-fat/sucrose diet, 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 suggest that IL-33 contributes to the maintenance of the normal pool of ST2+ Tregs in the VAT, and that therapeutic administration of IL-33 results in multiple anti-obesity effects, including the reversal of VAT inflammation and alleviation of insulin resistance.

Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes

“…In obesity, IL-33 plays a protective role in adipose tissue inflammation and insulin resistance (9,41). IL-33 induces the homeostasis and function of ST2-expressing ILC2s and Tregs (9,42). However, the source of IL-33 in adipose tissue was unclear.…”

Obesity-Associated Adipose Tissue Inflammation and Transplantation

“…Specifically, AT Tregs express elevated levels of IL-10, GATA3, CCR4, and the ST2 chain of the IL-33 receptor. The expression of all of these proteins on Tregs is diminished in obese AT (19)(20)(21)(22)(23). Diphtheria toxinmediated depletion of Tregs results in AT inflammation and insulin resistance (19), indicating that Tregs have a key role in maintaining metabolic homeostasis.…”

“…Diphtheria toxinmediated depletion of Tregs results in AT inflammation and insulin resistance (19), indicating that Tregs have a key role in maintaining metabolic homeostasis. The unique phenotype of AT Tregs seems to be driven at least partly by IL-33, because the administration of exogenous IL-33 induces proliferation in AT Tregs, restores their classic Th2-like phenotype, and is sufficient to resolve obesity-associated AT inflammation (21)(22)(23). The question of whether the effects of IL-33 on Tregs are direct or indirect, however, requires further research because IL-33 also has major effects on eosinophils and ILC2s, which could feed back and result in the observed change in Treg phenotype (15).…”

TAB3 involves in hepatic insulin resistance through activation of MAPK pathway

“…Palmitate acid (PA) is one form of saturated FFAs, which is frequently used to induce insulin resistance (Gao et al, 2010;Zhang et al, 2010). Palmitate-induced insulin resistance often accompanied by chronic inflammatory responses (El-Bassossy and Watson, 2015;Han et al, 2015). The MAPK pathway is rapidly activated in response to the inflammatory cytokines like IL-1 and TNF-a (Hazeldine et al, 2015;Luck et al, 2015).…”