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Molecular and Cellular Biology, September 2007, p. 6497-6505, Vol. 27, No. 18
0270-7306/07/$08.00+0     doi:10.1128/MCB.00679-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Peripheral Disruption of the Grb10 Gene Enhances Insulin Signaling and Sensitivity In Vivo

Departments of Pharmacology,¹ Medicine,² Biochemistry,³ Cellular and Structural Biology,⁵ Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229,⁶ Mammalian Genetics Section, GDDB, NIDDK, National Institutes of Health, Bethesda, Maryland 20892⁴

Received 18 April 2007/ Returned for modification 20 June 2007/ Accepted 28 June 2007

Grb10 is a pleckstrin homology and Src homology 2 domain-containing protein that interacts with a number of phosphorylated receptor tyrosine kinases, including the insulin receptor. In mice, Grb10 gene expression is imprinted with maternal expression in all tissues except the brain. While the interaction between Grb10 and the insulin receptor has been extensively investigated in cultured cells, whether this adaptor protein plays a positive or negative role in insulin signaling and action remains controversial. In order to investigate the in vivo role of Grb10 in insulin signaling and action in the periphery, we generated Grb10 knockout mice by the gene trap technique and analyzed mice with maternal inheritance of the knockout allele. Disruption of Grb10 gene expression in peripheral tissues had no significant effect on fasting glucose and insulin levels. On the other hand, peripheral-tissue-specific knockout of Grb10 led to significant overgrowth of the mice, consistent with a role for endogenous Grb10 as a growth suppressor. Loss of Grb10 expression in insulin target tissues, such as skeletal muscle and fat, resulted in enhanced insulin-stimulated Akt and mitogen-activated protein kinase phosphorylation. Hyperinsulinemic-euglycemic clamp studies revealed that disruption of Grb10 gene expression in peripheral tissues led to increased insulin sensitivity. Taken together, our results provide strong evidence that Grb10 is a negative regulator of insulin signaling and action in vivo.

Published ahead of print on 9 July 2007.

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