Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk

Abstract

Objective: Reduced numbers of regulatory T (T reg ) cells have been observed in visceral adipose tissue of obese mice and humans. However, it is unknown whether human obesity affects circulating Treg cells and whether their number is associated with markers of systemic inflammation or glucose intolerance. Design and Methods: Peripheral blood mononuclear cells were isolated from venous blood of obese (BMI ! 27 kg/m 2 ; n ¼ 30) and nonobese (BMI ! 27 kg/m 2 ; n ¼ 13) individuals and analyzed using flow cytometry for the expression of CD4, CD25, and Foxp3. Results: Reduced circulating T reg -cell numbers were detected in obese compared with nonobese study participants (P ¼ 0.038). Circulating CD4 þ CD25 þ CD127 À Foxp3 T reg cells inversely correlated with body weight (P ¼ 0.009), BMI (P ¼ 0.004) and plasma leptin levels (P ¼ 0.004) and were reduced in subjects with hsCRP ! 3.0 mg/L (P ¼ 0.034) or HbA1c ! 5.5% (P < 0.005). Receiver operating characteristic curve analysis revealed a cutoff of circulating Treg cells < 1.06% to be predictive for hsCRP levels ! 3.0 mg/L, and logistic regression showed that the risk of having hsCRP levels ! 3.0 mg/L was increased 9.6-fold (P ¼ 0.008), if T reg cells were below this threshold. The T reg cutoff for HbA1c levels ! 5.5% was 0.73%, and this cutoff also predicted an increased risk of having elevated levels of both hsCRP and HbA1c, if only obese subjects were examined. Conclusion: Our findings thus reveal an association between circulating T reg cells and measures of adiposity, inflammation, and glucose intolerance. Although further prospective studies are needed, we present data suggesting that the determination of T reg cells might be useful to identify obese subjects at increased risk of developing cardiovascular and/or metabolic complications.

Association of Soluble Fibrinogen-like Protein 2 with the Severity of Coronary Artery Disease

“…This is consistent with what has been described in other conditions with low-grade inflammation, such as obesity, where decreased Treg levels in individuals exhibiting elevated markers of systemic inflammation or impaired glucose tolerance were observed (28). These results suggest that the determination of the number of circulating Tregs using flow cytometry might be a useful indicator of the severity of atherosclerosis.…”

Peripheral mononuclear blood cells contribute to the obesity-associated inflammatory state independently of glycemic status: involvement of the novel proinflammatory adipokines chemerin, chitinase-3-like protein 1, lipocalin-2 and osteopontin

“…In addition, an association between white blood cell subtypes and measures of insulin resistance has been recently described (Lee et al 2014). Importantly, obese patients exhibit reduced immune regulatory T (Tregs) cells (Wagner et al 2013), and crucial defense against inappropriate immune responses operating in contexts of inflammation (Feuerer et al 2009;Sakaguchi et al 2008).…”

Female PAPP-A knockout mice are resistant to metabolic dysfunction induced by high-fat/high-sucrose feeding at middle age

“…IL-6 is elevated by high insulin levels and TNF-α in plasma and WAT, and it impacts insulin signaling by switching tyrosine to serine phosphorylation of the insulin receptor substrate-1 (IRS-1) (Fasshauer et al 2003). Furthermore, IL-2 induces low-grade inflammation through the activation of adipocytes and type 1 T-helper (Th1) cell migration promoting insulin resistance (Wagner et al 2013;Olefsky and Glass 2010;Gordon 2003). Our data show that PAPP-A KO female mice fed a combined HFHS diet have lower levels of inflammatory cytokines IL-2, IL-6, and TNF-α when compared to their N littermates fed an HFHS diet, thus escaping "obesity-linked inflammatory diseases."…”