Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation.

OBJECTIVE

Endothelial adhesion molecules like E-selectin play an important role in leukocyte recruitment and development of atherosclerotic plaque. E-selectin is increased in obesity, yet little is known regarding the specific factors contributing to elevated E-selectin in obesity and whether tumour necrosis factor alpha (TNF-alpha) increases E-selectin in vivo in this population. The objectives of this study were to: (1) determine the body composition, metabolic and inflammatory factors associated with increased E-selectin and (2) determine the role of TNF-alpha in the physiological regulation of E-selectin by antagonism of TNF-alpha with etanercept among obese subjects.

METHODS

E-selectin levels, body composition, metabolic parameters and inflammatory cytokines were assessed in 51 obese subjects and 37 non-obese healthy controls. Obese subjects were randomized to etanercept 50 mg weekly or placebo for 4 weeks. Changes in E-selectin were compared between treatment groups.

RESULTS

Obese subjects had higher E-selectin than non-obese controls (47.4 [32.7-58.8] vs. 27.2 [20.3-42.1] ng/ml, obese vs. non-obese, P < 0.0001). E-selectin was significantly associated with multiple body composition measures and metabolic parameters, along with specific measures of TNF-alpha activation, including soluble tumour necrosis factor receptors 1 (P = 0.03) and 2 (P = 0.02). In multivariate modelling, visceral adipose tissue, but not other measures of body composition, remained significantly associated with E-selectin. Among obese subjects, treatment with etanercept significantly decreased E-selectin (-5.7+/- 8.7 vs. 0.5+/- 6.0 ng/ml, etanercept vs. placebo, P = 0.005).

CONCLUSIONS

E-selectin is increased in obesity, in relationship to increased visceral adiposity and markers of TNF-alpha activation. TNF-alpha antagonism with etanercept reduces E-selectin in obese subjects, providing evidence that the systemic circulatory release of E-selectin is regulated at least in part by TNF-alpha in obesity.