Role of resistin in diet-induced hepatic insulin resistance
Evan D. Muse, … , Philipp E. Scherer, Luciano Rossetti
Evan D. Muse, … , Philipp E. Scherer, Luciano Rossetti
Published July 15, 2004
Citation Information: J Clin Invest. 2004;114(2):232-239. https://doi.org/10.1172/JCI21270.
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Article Metabolism

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.

Authors

Evan D. Muse, Silvana Obici, Sanjay Bhanot, Brett P. Monia, Robert A. McKay, Michael W. Rajala, Philipp E. Scherer, Luciano Rossetti

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Treatment with resistin ASO normalized plasma resistin levels in HF-fed ...
Treatment with resistin ASO normalized plasma resistin levels in HF-fed mice. (A) Experimental design for treatment with resistin ASO and clamp studies. Mice on HF diet for 3 weeks received an i.p. injection of resistin ASO (RsASO) or control ASO (ConASO) 7 and 3 days before the insulin-clamp studies. Intravenous catheters were inserted into the jugular vein 3 days before the clamp procedure. (B) Plasma insulin levels at the end of insulin clamp. Insulin levels were similar in all experimental groups. (C) Plasma resistin levels. Circulating resistin levels are significantly increased in mice on HF diet (black bar) as compared with mice on SC (white bar). Treatment with resistin ASO significantly decreased circulating resistin levels to those of SC-fed mice. Finally, infusion of recombinant mouse resistin acutely restored circulating resistin levels (HF + RsASO + i.v. Rs) to those observed in the HF-fed mice treated with control ASO. (D) Increased liver TGs with HF diet. Hepatic TG content was increased twofold by HF diet, whereas treatment with resistin ASO or acute infusion of recombinant resistin did not significantly altered hepatic TG levels. *P < 0.01 vs. SC group; #P < 0.01 vs. HF + ConASO; P < 0.01 vs. HF + RsASO. ww, wet weight.