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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/E1067    most recent 90714.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liu, X. Articles by Liu, F. Search for Related Content PubMed PubMed Citation Articles by Liu, X. Articles by Liu, F.

Downregulation of Grb2 contributes to the insulin-sensitizing effect of calorie restriction

Departments of ¹Pharmacology, ²Biochemistry, and ⁴Cellular and Structural Biology, and ³the Barshop Center for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, Texas; ⁵The Second Xiangya Hospital of Central South University, Hunan, People's Republic of China

Submitted 21 August 2008 ; accepted in final form 11 February 2009

Calorie restriction (CR) alleviates insulin resistance and has a beneficial effect on numerous metabolic disorders, yet the underlying mechanism has not been fully elucidated. In the present study, we found that CR of mice (60% of the diet consumption compared with ad libitum mice) reduces the expression levels of Grb2 in skeletal muscle, an insulin target tissue that accounts for 85% of insulin-stimulated blood glucose clearance. To determine whether Grb2 downregulation contributes to increased insulin sensitivity in the regulation of glucose metabolism, we generated C₂C₁₂ cell lines in which the expression of Grb2 is suppressed by RNA interference. Suppressing Grb2 expression in C₂C₁₂ myoblasts enhances insulin-stimulated insulin receptor substrate (IRS)-1, tyrosine phosphorylation, and Akt phosphorylation, which is associated with decreased IRS-1 serine phosphorylation at residues 307, 612, and 636/639. In addition, reducing Grb2 expression levels increased insulin-stimulated glucose uptake in C₂C₁₂ myotubes. Reduced IRS-1 serine phosphorylation is also found in Grb2^+/– heterozygous knockout mice, which is associated with enhanced insulin signaling and resistance to high-fat diet-induced glucose and insulin intolerance. All together, our results suggested that reducing the expression levels of Grb2 provides a mechanism by which CR increases insulin sensitivity in vivo.

mitogen-activated protein kinase; phosphoinositide 3-kinase; insulin sensitivity