TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome

J Clin Endocrinol Metab. 2011 Jan;96(1):E146-50. doi: 10.1210/jc.2010-1170. Epub 2010 Nov 3.


Context and objective: Obesity is associated with activation of the TNF-α system, increased inflammatory markers, and insulin resistance. Although studies in rodents suggest that attenuation of TNF activity improves glucose homeostasis, the effect of prolonged inhibition of TNF-α with etanercept on inflammation and glucose homeostasis in a human model of obesity is not known.

Design and participants: Forty obese subjects with features of metabolic syndrome were randomized to etanercept or placebo, 50 mg twice weekly for 3 months, followed by 50 mg once weekly for 3 months.

Outcome measures: Subjects underwent oral glucose tolerance testing and measurement of serum inflammatory biomarkers and adipokines. Subcutaneous fat biopsy was performed in a subset for measurement of adipokine and TNF-α mRNA expression.

Results: Visceral adiposity was significantly associated with serum concentrations of TNF receptor 1 (TNFR1), TNFR2, and vascular cell adhesion molecule-1 and adipose tissue expression of TNF-α and SOCS-3 (all P < 0.05). Insulin resistance as assessed by homeostasis model assessment was significantly associated with TNFR1, C-reactive protein, IL-6, and soluble intracellular adhesion molecule-1 (sICAM-1) (all P < 0.05). Etanercept significantly improved fasting glucose (treatment effect vs. placebo over 6 months, -10.8 ± 4.4%, P = 0.02). Etanercept also increased the ratio of high molecular weight adiponectin to total adiponectin (+22.1 ± 9.2% vs. placebo, P = 0.02), and decreased levels of sICAM-1 (-11 ± 2% vs. placebo, P < 0.0001). In contrast, body composition, lipids, C-reactive protein, and IL-6 were unchanged after 6 months.

Conclusions: Prolonged therapy with etanercept improved fasting glucose, increased the ratio of high molecular weight to total adiponectin, and decreased sICAM-1 in obese subjects with abnormal glucose homeostasis and significant subclinical inflammation.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / blood*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Biomarkers / blood
  • Blood Glucose
  • Body Composition
  • Etanercept
  • Female
  • Glucose Tolerance Test
  • Humans
  • Immunoglobulin G / therapeutic use*
  • Male
  • Metabolic Syndrome / blood
  • Metabolic Syndrome / complications
  • Metabolic Syndrome / therapy*
  • Obesity / blood
  • Obesity / complications
  • Obesity / therapy*
  • Receptors, Tumor Necrosis Factor / therapeutic use*
  • Subcutaneous Fat / metabolism*
  • Treatment Outcome


  • Adipokines
  • Anti-Inflammatory Agents, Non-Steroidal
  • Biomarkers
  • Blood Glucose
  • Immunoglobulin G
  • Receptors, Tumor Necrosis Factor
  • Etanercept