Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters

Abstract

Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. How does fat inflammation escape the powerful armamentarium of cells and molecules normally responsible for guarding against a run-away immune response? Regulatory CD4 + T cells expressing the transcription factor Foxp3 (termed T reg cells) are a lymphocyte lineage specialized in controlling immunologic reactivity. T reg cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but were strikingly and specifically reduced at this site in insulin-resistant models of obesity. In loss-offunction and gain-of-function experiments, T reg cells regulated the inflammatory state of adipose tissue and insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly impacted on the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These findings open the door to harnessing the anti-inflammatory properties of T reg cells to inhibit elements of the metabolic syndrome.

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…These data suggest that regulatory T cells may repress adipose tissue inflammation and play a role in providing protection against insulin resistance-induced inflammation linked to obesity [33,37]. The number of many other immune cells is also modified in adipose tissue during obesity and could regulate inflammation and insulin resistance [4] (Figure 1).…”

“…Infiltrating lymphocytes precede macrophage populations in obese adipose tissue concomitant with early insulin resistance and may play a role in adipose tissue inflammation by modifying the number and the activation state of adipose tissue macrophages [37][38][39][40]. In mouse models of obesity, an increased numbers of cytotoxic CD8+ effector cells is suspected to initiate the recruitment and activation of adipose tissue macrophages and promote pro-inflammatory cascades associated with insulin resistance [38,40].…”

“…Obesity also induces modification in the balance between pro-inflammatory (T helper 1 and T helper 17 lymphocytes) and antiinflammatory (T helper 2 and regulatory T lymphocytes) CD4+ cells subsets, leading to secretion of cytokines from newly recruited adipose tissue macrophages [39][40][41]. Of particular interest, the number of anti-inflammatory regulatory T lymphocytes decreases with obesity in adipose tissue of both mice and humans [37,39,40] and even more in obese patients with metabolic syndrome [33]. The regulatory T lymphocytes express high amount of the antiinflammatory cytokine IL-10 which inhibit macrophage migration and induce the differentiation of M2 macrophages [35,37].…”

“…Of particular interest, the number of anti-inflammatory regulatory T lymphocytes decreases with obesity in adipose tissue of both mice and humans [37,39,40] and even more in obese patients with metabolic syndrome [33]. The regulatory T lymphocytes express high amount of the antiinflammatory cytokine IL-10 which inhibit macrophage migration and induce the differentiation of M2 macrophages [35,37]. A boost in the number of these cells in obese mice can improve insulin sensitivity and reduce macrophage infiltration in adipose tissue [37].…”

“…The regulatory T lymphocytes express high amount of the antiinflammatory cytokine IL-10 which inhibit macrophage migration and induce the differentiation of M2 macrophages [35,37]. A boost in the number of these cells in obese mice can improve insulin sensitivity and reduce macrophage infiltration in adipose tissue [37].…”