title: Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation.
abstract: 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.
authors.affiliation: Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Markella V
authors.initials: MV
authors.lastname: Zanni
authors.forename: Takara L
authors.initials: TL
authors.lastname: Stanley
authors.forename: Hideo
authors.initials: H
authors.lastname: Makimura
authors.forename: Cindy Y
authors.initials: CY
authors.lastname: Chen
authors.forename: Steven K
authors.initials: SK
authors.lastname: Grinspoon
mesh_terms: D000328:Adult; D001823:Body Composition; D019040:E-Selectin / Q000378:metabolism*; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism / Q000503:physiopathology*; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D019040:E-Selectin; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept