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.
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.


METHODS
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.


METHODS
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.
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Takara L
TL
Stanley
Markella V
MV
Zanni
Stine
S
Johnsen
Sarah
S
Rasheed
Hideo
H
Makimura
Hang
H
Lee
Victor K
VK
Khor
Rexford S
RS
Ahima
Steven K
SK
Grinspoon
D054392:Adipokines / Q000097:blood*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose; D001823:Body Composition; D000068800:Etanercept; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000150:complications / Q000628:therapy*; D009765:Obesity / Q000097:blood / Q000150:complications / Q000628:therapy*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D050151:Subcutaneous Fat / Q000378:metabolism*; D016896:Treatment Outcome
D054392:Adipokines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D001786:Blood Glucose; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept