Role of resistin in diet-induced hepatic insulin resistance

Abstract

Resistin is an adipose-derived hormone postulated to link adiposity to insulin resistance.To determine whether resistin plays a causative role in the development of diet-induced insulin resistance, we lowered circulating resistin levels in mice by use of a specific antisense oligodeoxynucleotide (ASO) directed against resistin mRNA and assessed in vivo insulin action by the insulin-clamp technique.After 3 weeks on a high-fat (HF) diet, mice displayed severe insulin resistance associated with an approximately 80% increase in plasma resistin levels.In particular, the rate of endogenous glucose production (GP) increased more than twofold compared with that in mice fed a standard chow.Treatment with the resistin ASO for 1 week normalized the plasma resistin levels and completely reversed the hepatic insulin resistance.Importantly, in this group of mice, the acute infusion of purified recombinant mouse resistin, designed to acutely elevate the levels of circulating resistin up to those observed in the HF-fed mice, was sufficient to reconstitute hepatic insulin resistance.These results provide strong support for a physiological role of resistin in the development of hepatic insulin resistance in this model.Nonstandard abbreviations used: AMP-activated protein kinase (AMPK); antisense oligonucleotide (ASO); gluconeogenesis (GNG); glucose infusion rate (GIR); glucose-6-phosphatase (G6Pase); glycogen synthase kinase 3 (GSK3); high-fat (HF); intraperitoneal (i.p.); open reading frame (ORF); peroxisome proliferator-activated receptor-γ (PPAR-γ); phosphoenolpyruvate (PEP); phosphoenolpyruvate carboxykinase (PEPCK); rate of endogenous glucose production (GP); rate of glucose appearance (Ra); rate of glucose disappearance (Rd); standard chow (SC); triglyceride (TG); type 2 diabetes mellitus (DM2); uridinediphospho-glucose (UDP-glucose).Conflict of interest: S. Bhanot, B.P. Monia, and R.A. McKay are employees of ISIS Pharmaceuticals, which has an interest in developing antisense therapeutics to treat diabetes and other diseases.