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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-09-0181v1 203/3/337    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zheng, Y. Articles by Sun, X. J. PubMed PubMed Citation Articles by Zheng, Y. Articles by Sun, X. J.

Y Zheng, Medicine, The University of Chicago, Chicago, United States
W Zhang, Medicine, The University of Chicago, Chicago, United States
E Pendleton, Medicine, The University of Chicago, Chicago, United States
S Leng, College of Health Professions, Syosset, United States
J Wu, Cell Signaling Technology, Inc., Beverly, United States
R Chen, HumanZyme, Chicago, United States
X Sun, Medicine, The University of Chicago, Chicago, 60637, United States

Xiao Jian Sun, Email: xsun{at}medicine.bsd.uchicago.edu

Caloric restriction (CR) improves obesity-related insulin resistance through undefined molecular mechanisms. IRS-1 serine/threonine kinases have been proposed to modulate insulin sensitivity through phosphorylation of IRS-proteins. The aim of this study is to test the hypothesis that changes in the activity of IRS-1 serine/threonine kinases may underlie the molecular mechanism of CR in improving insulin sensitivity. Obese and lean Zucker rats were subjected to 40% CR or allowed to feed ad libitum for 20 weeks; body weight and insulin sensitivity were monitored throughout this period. The activity of IRS-1 serine/threonine kinases- including JNK, ERK, mTOR/p70S6K, GSK3ß, AMPK, and PKC in liver tissue extracts was measured by an in vitro kinase assay using various GST-IRS-1 fragments as substrates, while phosphorylation of IRS-1 and serine kinases was determined by western blotting using phosphospecific antibodies. CR in obese rats significantly reduced body weight and increased insulin sensitivity compared to ad libitum controls. Serine kinase activity towards IRS-1S612 (corresponding to S616 in human IRS-1) and IRS-1S632/635 (corresponding to S636/639 in human IRS-1) was increased in obese rats compared to lean littermates, and was markedly decreased following CR. Concomitantly, obesity increased and CR decreased the activity of hepatic ERK and p70 S6K against IRS-1. The close association between the activity of hepatic ERK and p70 S6K with insulin resistance suggests an important role for ERK and p70 S6Kin the development of insulin resistance, presumably via phosphorylation of IRS-proteins.