T-Cell Accumulation and Regulated on Activation, Normal T Cell Expressed and Secreted Upregulation in Adipose Tissue in Obesity

Abstract

Background-Obesity is associated with chronic inflammation, which includes increased macrophage accumulation in adipose tissue (AT) and upregulation of chemokines and cytokines. T cells also play important roles in chronic inflammatory diseases such as atherosclerosis but have not been well studied in obesity. Methods and Results-Flow cytometric analysis showed higher numbers of T cells and macrophages in AT of diet-induced obese insulin-resistant male mice than in lean mice and obese females (PϽ0.05). RNase protection assay, ELISA, and flow cytometry indicated gender-dependent upregulation of mRNA and protein levels of regulated on activation, normal T cell expressed and secreted (RANTES) and its receptor CCR5 in AT of obese mice. Adipocytes, stromal/vascular cells from mouse AT, and human and murine adipocytes expressed RANTES. RANTES mRNA levels were negatively correlated with adiponectin in mouse AT. Adiponectin-deficient mice fed high-fat diet showed higher RANTES mRNA levels in AT than wild-type mice. Activated T cells coincubated with preadipocytes in vitro significantly suppressed preadipocyte-to-adipocyte differentiation. Obese humans with metabolic syndrome had higher mRNA levels of RANTES and CCR5 in subcutaneous AT than lean humans. RANTES and CCR5 mRNA levels were significantly higher in visceral than subcutaneous AT of morbidly obese humans. RANTES mRNA levels were positively correlated with CD3 and CD11b in human visceral AT. Conclusions-Obesity is associated with increased accumulation of T cells and macrophages in AT, which may play important roles in obesity-related disease by influencing preadipocyte/adipocyte functions. RANTES is an adipokine that is upregulated in AT by obesity in both mice and humans.

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

“…In accordance with recent data [17,18], we found an increase in CD3 + T cells in SAT from obese women compared with lean women.…”

“…CD40L is produced by activated CD4 + T cells [14]. Obesity in mice and humans has been associated recently with T cell accumulation in adipose tissue [15][16][17][18]. In obese mice, accumulation of proinflammatory T lymphocytes in visceral adipose tissue precedes the appearance of macrophages, suggesting that T lymphocytes play an important part in the initiation of adipose tissue inflammation, as well as in the development of insulin resistance [16].…”

“…In obese mice, accumulation of proinflammatory T lymphocytes in visceral adipose tissue precedes the appearance of macrophages, suggesting that T lymphocytes play an important part in the initiation of adipose tissue inflammation, as well as in the development of insulin resistance [16]. Furthermore, it appears that T lymphocytes have an active role in adipose tissue biology because they strongly inhibit the differentiation of 3T3-L1 preadipocytes into adipocytes [18].…”

Downregulation of genes involved in NFκB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: the GENOBIN study

“…In obesity, the effect of weight loss on lowering circulating concentrations of TNF-α and its expression in sites of production [9,48,49] could have an impact on the decrease in TNF receptor mRNA expression, with consequences on the activation of NFκB [35,50]. Moreover, the associations between both the downregulation of IL1B [9] and the changes in TLR4, TLR2, TNFRSF1A or CCL5 mRNA expression in PBMCs and the improvement of S I after weight loss in the present study supports this hypothesis.…”

“…Indeed, in humans, obesity is associated with increased NFκB binding activity and IKBKB expression in circulating mononuclear cells [12,13]. Macrophage infiltration in adipose tissue has been linked to obesity-related inflammation and insulin resistance [33,34], and upregulation of CCL5 in visceral fat of obese individuals with the metabolic syndrome has recently been associated with markers of T cells and macrophages in this tissue [35]. Although we cannot directly conclude this, the correlation between the decrease in CCL5 expression and that in IKBKB and ICAM1 expression suggests that, besides NFκB activation, an interplay occurs between markers of endothelial function in immune cells on the one hand, and insulin and glucose metabolism after weight loss on the other.…”