Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life.
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.
Smith
Florentia M
FM
University of Bath, Developmental Biology Program and Centre for Regenerative Medicine, Department of Biology and Biochemistry, Claverton Down, Bath BA2 7AY, United Kingdom.
Holt
Lowenna J
LJ
Garfield
Alastair S
AS
Charalambous
Marika
M
Koumanov
Francoise
F
Perry
Mark
M
Bazzani
Reto
R
Sheardown
Steven A
SA
Hegarty
Bronwyn D
BD
Lyons
Ruth J
RJ
Cooney
Gregory J
GJ
Daly
Roger J
RJ
Ward
Andrew
A
D052436:Adipose Tissue, White / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D000831:Animals, Newborn; D001823:Body Composition; D001835:Body Weight; D004789:Enzyme Activation; D005247:Feeding Behavior; D051383:GRB10 Adaptor Protein / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics*; D005947:Glucose / Q000032:analysis / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D019000:Phosphotyrosine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
D007328:Insulin; D020738:Leptin; D051383:GRB10 Adaptor Protein; D019000:Phosphotyrosine; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose