Potential Role of Regulatory T Cells in Reversing Obesity-Linked Insulin Resistance and Diabetic Nephropathy

Eller, Kathrin; Kirsch, Alexander H.; Wolf, Anna Maria; Sopper, Sieghart; Tagwerker, Andrea; Stanzl, Ursula; Wolf, Dominik; Patsch, Wolfgang; Rosenkranz, Alexander R.; Eller, Philipp

doi:10.2337/db11-0358

Cited by 277 publications

(264 citation statements)

References 34 publications

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“…This phenomenon suggests that the WAT Treg population may undergo antigen selection [30]. In agreement with these studies, WAT Treg numbers are decreased in the WAT of obese mice [53,54], whereas adoptive transfer of Tregs or their targeted activation and proliferation improved WAT inflammation and ameliorated insulin resistance in ob/ob mice [54,55].…”

Section: Regulatory T Cellssupporting

confidence: 76%

Lymphocytes in obesity-related adipose tissue inflammation

et al. 2012

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Inflammation in the white adipose tissue (WAT) is considered a major player in the development of insulin resistance. The role of macrophages accumulating in the WAT during obesity, promoting WAT inflammation and insulin resistance is well established. In contrast, less is known about the role of lymphocytes. Recent studies have implicated different lymphocyte subsets in WAT inflammation. For instance, cytotoxic CD8 + T cells infiltrating the WAT may contribute to the recruitment, differentiation and activation of macrophages. On the other hand, a differential role for CD4 + Th1 and CD4 + Th2 cells has been suggested.Levels of WAT regulatory T cells decrease during the course of obesity and may represent a crucial factor for the maintenance of insulin sensitivity. Moreover, activation of natural killer T cells, an innate-like T cell population, which recognises lipid antigens, promotes insulin resistance and WAT inflammation. Finally, B cells may infiltrate WAT very early in response to high-fat feeding and worsen glucose metabolism through modulation of T cells and the production of pathogenic antibodies. These interesting new findings however bear controversies and introduce novel, yet unanswered, questions. Here, we review and discuss the impact of the different lymphocyte subsets in obesityrelated WAT inflammation and attempt to identify the open questions to be answered by future studies.

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Section: Regulatory T Cellssupporting

confidence: 76%

Lymphocytes in obesity-related adipose tissue inflammation

et al. 2012

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“…These findings have led to the hypothesis that poor Treg function in obese VAT is a major factor contributing to chronic VAT inflammation. In support of this possibility, treatments that enhance Tregs, such as administration of anti-CD3 (5), or IL-2 anti-IL-2 complex (6), or adoptive transfer of Tregs themselves (8), can improve insulin sensitivity.…”

mentioning

confidence: 99%

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

Han

Denroche

et al. 2015

The Journal of Immunology

153

162

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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.

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“…It was shown that repertoire of T cells in adipose tissue vary depending on the degree of obesity [21]. There is a hypothesis that peripherally induced FoxP3+ Treg cells may be recruited in the inflamed VAT, while thymic-derived natural Tregs are represented in VAT during obesity insufficiently [47]. We may speculate that there are two possible ways to explain the reverse correlation between FoxP3+ Treg numbers and VAI observed in DM2 patients in our study.…”

Section: Discussionmentioning

confidence: 55%

“…In this case systemic decrease of Treg cells may be associated with the increase of adipose tissue volume and elevated local production of inflammatory cytokines and adipokines. Or the decline in peripheral blood numbers of Tregs may be the consequence of FoxP3+ Tregs recruitment to adipose tissue in order to control the local inflammation: the process which tends to proceed more actively with the increase of visceral adiposity, estimated by elevated VAI in our study [47].…”

Section: Discussionmentioning

confidence: 83%