Cytokine modulation by etanercept ameliorates metabolic syndrome and its related complications induced in rats administered a high-fat high-fructose diet

Abstract

The aim of the present study was to investigate the effect of etanercept (ETA)—an anti-tumor necrosis factor α (TNF-α) monoclonal antibody—on metabolic disorders such as obesity, hypertension, dyslipidemia, and insulin resistance associated with the metabolic syndrome (MS). MS was induced in rats via high-fat high-fructose (HFHF) administration for 8 weeks. Rats were divided into three groups: negative control, HFHF model, and ETA-treated groups [HFHF + ETA (0.8 mg/kg/twice weekly, subcutaneously) administered in the last 4 weeks]. ETA effectively diminished the prominent features of MS via a significant reduction in the percent body weight gain along with the modulation of adipokine levels, resulting in a significant elevation of serum adiponectin consistent with TNF-α and serum leptin level normalization. Moreover, ETA enhanced dyslipidemia and the elevated blood pressure. ETA managed the prominent features of MS and its associated complications via the downregulation of the hepatic inflammatory pathway that induces nonalcoholic steatohepatitis (NASH)—from the expression of Toll-like receptor 4, nuclear factor kappa B, and TNF-α until that of transforming growth factor—in addition to significant improvements in glucose utilization, insulin sensitivity, and liver function parameter activity and histopathological examination. ETA was effective for the treatment of all prominent features of MS and its associated complications, such as type II diabetes mellitus and NASH.

Immune Disorders Connecting Type2 Diabetes and Cardiovascular Complications

“…TNFα deficiency curtailed atherosclerotic lesion formation, possibly through attenuating macrophage foam cell formation and deposition in the arterial wall intima [46][47][48][49].Anti-TNFα antibody treatment restored the impaired coronary artery dilation in Db/Db mice through dampening NFkB (nuclear factor kappa B) mediated proinflammatory signaling [50]. Additional studies showed that Anti-TNFα ameliorated hypertension induced by a high-fat high-fructose diet in rat [51]. Subsequent mechanistic studies revealed that TNFα impaired the production of NO (nitro oxide) production and increased superoxide generation through NADPH oxidase in various vascular beds [48,52,53].…”