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This Article Full Text Full Text (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.

Section of Endocrinology, The University of Chicago, 900 E 57th Street, KCBD Room 8122, Chicago, Illinois 60637, USA
¹ HumanZyme, Chicago, Illinois 60612, USA
² Cell Signaling Technology, Inc., Beverly, Massachusetts 01915, USA

(Correspondence should be addressed to X J Sun; Email: xsun{at}medicine.bsd.uchicago.edu)

Calorie restriction (CR) improves obesity-related insulin resistance through undefined molecular mechanisms. Insulin receptor substrate (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 IRS1 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 (AL) for 20 weeks; body weight and insulin sensitivity were monitored throughout this period. The activity of IRS1 serine/threonine kinases – including JNK, ERK, MTOR/p70^S6K (RPS6KB1 as listed in the MGI Database), glycogen synthase kinase 3β (GSK3B), AMPK (PRKAA1 as listed in the MGI Database), and protein kinase C (PRKCQ) in liver tissue extracts was measured by an in vitro kinase assay using various glutathione-S-transferase (GST)–IRS1 fragments as substrates, while phosphorylation of IRS1 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 AL controls. Serine kinase activity toward IRS1^S612 (corresponding to S616 in human IRS1) and IRS1^S632/635 (corresponding to S636/639 in human IRS1) 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 IRS1. The close association between the activity of hepatic ERK and p70^S6K with insulin resistance suggests an important role for ERK and p70^S6K in the development of insulin resistance, presumably via phosphorylation of IRS proteins.