Impact of Oxidative Stress and Peroxisome Proliferator-activated Receptor Gamma Coactivator-1alpha in Hepatic Insulin Resistance

Overview

Journal Diabetes

Specialty Endocrinology

Date 2008 May 20

PMID 18487450

Citations 41

Authors

Naoki Kumashiro

Yoshifumi Tamura

Toyoyoshi Uchida

Takeshi Ogihara

Yoshio Fujitani

Takahisa Hirose

Hideki Mochizuki

Ryuzo Kawamori

Hirotaka Watada

Affiliations

Soon will be listed here.

Abstract

Objective: Recent studies identified accumulation of reactive oxygen species (ROS) as a common pathway causing insulin resistance. However, whether and how the reduction of ROS levels improves insulin resistance remains to be elucidated. The present study was designed to define this mechanism.

Research Design And Methods: We investigated the effect of overexpression of superoxide dismutase (SOD)1 in liver of obese diabetic model (db/db) mice by adenoviral injection.

Results: db/db mice had high ROS levels in liver. Overexpression of SOD1 in liver of db/db mice reduced hepatic ROS and blood glucose level. These changes were accompanied by improvement in insulin resistance and reduction of hepatic gene expression of phosphoenol-pyruvate carboxykinase and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), which is the main regulator of gluconeogenic genes. The inhibition of hepatic insulin resistance was accompanied by attenuation of phosphorylation of cAMP-responsive element-binding protein (CREB), which is a main regulator of PGC-1alpha expression, and attenuation of Jun NH(2)-terminal kinase (JNK) phosphorylation. Simultaneously, overexpression of SOD1 in db/db mice enhanced the inactivation of forkhead box class O1, another regulator of PGC-1alpha expression, without the changes of insulin-induced Akt phosphorylation in liver. In hepatocyte cell lines, ROS induced phosphorylation of JNK and CREB, and the latter, together with PGC-1alpha expression, was inhibited by a JNK inhibitor.

Conclusions: Our results indicate that the reduction of ROS is a potential therapeutic target of liver insulin resistance, at least partly by the reduced expression of PGC-1alpha.

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