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Molecular and Cellular Biology, August 2007, p. 5871-5886, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.02087-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mice with a Disruption of the Imprinted Grb10 Gene Exhibit Altered Body Composition, Glucose Homeostasis, and Insulin Signaling during Postnatal Life{triangledown}

Florentia M. Smith,1,{dagger} Lowenna J. Holt,2,{dagger} Alastair S. Garfield,1 Marika Charalambous,1,{ddagger} Francoise Koumanov,1 Mark Perry,3 Reto Bazzani,1 Steven A. Sheardown,4 Bronwyn D. Hegarty,5 Ruth J. Lyons,2 Gregory J. Cooney,5 Roger J. Daly,2 and Andrew Ward1*

University of Bath, Developmental Biology Program and Centre for Regenerative Medicine, Department of Biology and Biochemistry, Claverton Down, Bath BA2 7AY, United Kingdom,1 Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, NSW 2010, Australia,2 Departments of Anatomy and Academic Rheumatology, University of Bristol Vet School, Southwell St., Bristol BS2 8EJ, United Kingdom,3 GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, United Kingdom,4 Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, NSW 2010, Australia5

Received 8 November 2006/ Returned for modification 14 December 2006/ Accepted 22 May 2007

The Grb10 adapter protein is capable of interacting with a variety of receptor tyrosine kinases, including, notably, the insulin receptor. Biochemical and cell culture experiments have indicated that Grb10 might act as an inhibitor of insulin signaling. We have used mice with a disruption of the Grb10 gene (Grb10{Delta}2-4 mice) to assess whether Grb10 might influence insulin signaling and glucose homeostasis in vivo. Adult Grb10{Delta}2-4 mice were found to have improved whole-body glucose tolerance and insulin sensitivity, as well as increased muscle mass and reduced adiposity. Tissue-specific changes in insulin receptor tyrosine phosphorylation were consistent with a model in which Grb10, like the closely related Grb14 adapter protein, prevents specific protein tyrosine phosphatases from accessing phosphorylated tyrosines within the kinase activation loop. Furthermore, insulin-induced IRS-1 tyrosine phosphorylation was enhanced in Grb10{Delta}2-4 mutant animals, supporting a role for Grb10 in attenuation of signal transmission from the insulin receptor to IRS-1. We have previously shown that Grb10 strongly influences growth of the fetus and placenta. Thus, Grb10 forms a link between fetal growth and glucose-regulated metabolism in postnatal life and is a candidate for involvement in the process of fetal programming of adult metabolic health.

* Corresponding author. Mailing address: University of Bath, Developmental Biology Program and Centre for Regenerative Medicine, Department of Biology and Biochemistry, Claverton Down, Bath BA2 7AY, United Kingdom. Phone: 00(44)1225 386914. Fax: 00(44)1225 386779. E-mail: bssaw{at}bath.ac.uk

{triangledown} Published ahead of print on 11 June 2007.

{dagger} These authors have contributed equally to this work.

{ddagger} Present address: Department of Physiology, Development and Neuroscience, University of Cambridge, Anatomy Building, Downing Street, Cambridge CB2 3BY, United Kingdom.

Molecular and Cellular Biology, August 2007, p. 5871-5886, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.02087-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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