Search

Objective: Reduced numbers of regulatory T (Treg) 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/m2; n = 30) and nonobese (BMI ≥ 27 kg/m2; n = 13) individuals and analyzed using flow cytometry for the expression of CD4, CD25, and Foxp3. Results: Reduced circulating Treg-cell numbers were detected in obese compared with nonobese study participants (P = 0.038). Circulating CD4+CD25+CD127−Foxp3 Treg cells inversely correlated with body weight (P = 0.009), BMI (P = 0.004) and plasma leptin levels (P = 0.004) and were reduced in subjects with hsCRP ≥ 3.0 mg/L (P = 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 = 0.008), if Treg cells were below this threshold. The Treg 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 Treg cells and measures of adiposity, inflammation, and glucose intolerance. Although further prospective studies are needed, we present data suggesting that the determination of Treg cells might be useful to identify obese subjects at increased risk of developing cardiovascular and/or metabolic complications.

Objectives The purpose of this study was to examine the impact of obesity and weight loss on the angiogenic and regenerative capacity of endothelial progenitor cells (EPCs). Background EPCs participate in angiogenesis and tissue repair. Several cardiovascular risk factors are associated with EPC dysfunction. Methods Early outgrowth EPCs were isolated from 49 obese (age 42 ± 14 years; body mass index 42 ± 7 kg/m2) normoglycemic participants in a professional weight reduction program and compared with those from 49 age-matched lean controls. EPC function was tested both in vitro and in vivo. Results EPCs expanded from the obese possessed reduced adhesive, migratory, and angiogenic capacity, and mice treated with obese EPCs exhibited reduced EPC homing in ischemic hind limbs in vivo. EPCs from the obese subjects failed to respond to conditioned medium of lean controls or to potent angiogenic factors such as vascular endothelial growth factor. Although no differences existed between lean and obese EPCs regarding the surface expression of vascular endothelial growth factor or chemokine receptors, basal p38 mitogen-activated protein kinase (MAPK) phosphorylation was elevated in obese EPCs (3.7 ± 2.1-fold increase; p = 0.006). These cells also showed reduced secretion of the angiogenic chemokines interleukin-8 (p = 0.047) and monocyte chemoattractant protein-1 (p = 0.012). By inhibiting p38 MAPK, we could restore chemokine levels to those of lean control EPCs and also improve the angiogenic properties of obese EPCs. Accordingly, 6-month follow-up of 26 obese persons who achieved significant weight reduction revealed normalization of p38 MAPK phosphorylation levels and improved EPC function. Conclusions Obesity is associated with a reversible functional impairment of EPCs. This involves reduced secretion of angiogenic chemokines and increased basal phosphorylation of signaling molecules, notably p38 MAPK.

SummaryClinical studies have shown that elevated leptin levels are an independent cardiovascular risk factor. However, little is known about the existence of platelet resistance to leptin in the setting of obesity. We examined the effects of leptin on platelet aggregation in morbidly obese subjects (n=40; BMI, 41.6 ± 1.1 kg/m2; leptin, 49.7 ± 3.4 ng/ml) in comparison to normal-weight controls (n=36; BMI, 23.3 ± 0.4 kg/m2; leptin, 6.5 ± 0.7 ng/ml).The aggregatory response to increasing concentrations of adenosine diphosphate (ADP) (2, 3, 4, and 5 µM) was significantly increased in platelets from obese compared to lean donors, reflecting a left shift in the dose-response curve. Plasma leptin levels, but not BMI, were significantly higher in subjects with stronger (above the median) compared to weaker (below the median) platelet aggregation at all ADP concentrations tested. In further experiments, stimulation (preincubation) with leptin (500 ng/ml) promoted ADP-induced platelet aggregation by approximately 25%, and there was no difference between platelets from obese and those from lean donors regarding the responsiveness to leptin (p=0.99). Western blotting revealed that leptin induced phosphorylation of JAK2 and STAT3 to a similar extent in platelets from both groups. Expression of potential mediators of leptin resistance (SOCS3 and PTP1B) also did not differ in platelets from obese and control subjects. In conclusion, our data indicate that platelets from obese donors show increased aggregatory response to ADP, and that this might partly be the consequence of increased circulating leptin levels. Platelets from obese donors are not resistant to the enhancing effects of leptin on ADPinduced platelet aggregation.