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Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life

Abstract

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 (Grb10Delta2-4 mice) to assess whether Grb10 might influence insulin signaling and glucose homeostasis in vivo. Adult Grb10Delta2-4 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 Grb10Delta2-4 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.

Type Journal
ISBN 0270-7306 (Print)
Authors Smith, F. M.;Holt, L. J.;Garfield, A. S.;Charalambous, M.;Koumanov, F.;Perry, M.;Bazzani, R.;Sheardown, S. A.;Hegarty, B. D.;Lyons, R. J.;Cooney, G. J.;Daly, R. J.;Ward, A. :
Garvan Authors Prof Gregory Cooney
Publisher Name MOL CELL BIOL
Published Date 2007-01-01 00:00:00
Published Volume 27
Published Issue 16
Published Pages 5871-86
URL http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17562854
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?2286_11046/07 Smith MCB.pdf