Dr Zanni and Dr Stanley contributed equally to this work.
Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation
Article first published online: 31 OCT 2009
© 2010 Blackwell Publishing Ltd
Volume 73, Issue 1, pages 48–54, July 2010
How to Cite
Zanni, M. V., Stanley, T. L., Makimura, H., Chen, C. Y. and Grinspoon, S. K. (2010), Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation. Clinical Endocrinology, 73: 48–54. doi: 10.1111/j.1365-2265.2009.03741.x
- Issue published online: 14 JUN 2010
- Article first published online: 31 OCT 2009
- (Received 4 September 2009; returned for revision 1 October 2009; finally revised 7 October 2009; accepted 7 October 2009)
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.