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 (Grb10⌬2-4 mice) to assess whether Grb10 might influence insulin signaling and glucose homeostasis in vivo. Adult Grb10⌬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⌬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.Insulin controls glucose homeostasis by regulating protein, lipid, and carbohydrate metabolism. Cellular responses to insulin in target tissues, such as skeletal muscle, adipose tissue, and liver, are mediated via the insulin receptor (Insr) (reviewed in reference 51). Activation of the Insr results in tyrosine phosphorylation of intracellular docking proteins such as Shc and IRS-1 through IRS-4, which then bind specific Src homology 2 (SH2) domain-containing enzymes and adapters, leading to the activation of downstream signaling cascades. A critical event mediating insulin regulation of metabolic endpoints is the activation of phosphatidylinositol 3-kinase (PI3K). This stimulates the synthesis of phosphatidylinositol 3,4,5-triphosphate, which induces plasma membrane recruitment and subsequent phosphorylation of protein kinase B (also known as Akt), a key player in the regulation of glucose uptake and glycogen synthesis. Activation of the Insr and downstream signaling results in increased glucose uptake, utilization, and storage in adipose tissue and skeletal muscle, while decreased gluconeogenesis and glycogenolysis and increased glycogen synthesis occur in the liver (reviewed in reference 51). Resistance to these effects of insulin is a defining feature of type 2 diabetes, a polygenic disease afflicting over 110 million people worldwide. Impaired insulin action is also a feature of obesity and predisposes people to arteriosclerosis and cardiovascular diseases, facts which highlight its importance in human health. The fundamental role of the Insr in insulin action was demonstrated following targeted disruption of the receptor (1, 29). To dissect the contribution of individual tissues to gl...

Grb10 characterization in bovine cumulus oocyte complexes from different follicle sizes

“…Previous studies showed that Nrip1 plays an important role in controlling lipid and glucose metabolism (ROSELL et al, 2010). In agreement, a study using knockout mice with a disruption of the Grb10 gene was found to improve insulin sensitivity and to reduce adiposity (SMITH et al, 2007). An association of Nrip1 and Grb10 has not been described yet.…”

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

“…GRB10 has been found to protect the vascular endothelial growth factor receptor from ubiquitin-mediated degradation in HEK293 cells [45]. Although GRB10 has been identified as a negative regulator of the insulin receptor [10], IRS1 levels are markedly reduced in skeletal muscle from mice with a targeted disruption of either GRB10 alone, or combined with the related GRB14 protein [46,47]. Intriguingly, in muscle from the Grb10-knockout mouse, insulin-induced tyrosine phosphorylation of IRS1 was increased, whereas insulin-induced phosphorylation of AktSer473 was decreased [46].…”

“…Although GRB10 has been identified as a negative regulator of the insulin receptor [10], IRS1 levels are markedly reduced in skeletal muscle from mice with a targeted disruption of either GRB10 alone, or combined with the related GRB14 protein [46,47]. Intriguingly, in muscle from the Grb10-knockout mouse, insulin-induced tyrosine phosphorylation of IRS1 was increased, whereas insulin-induced phosphorylation of AktSer473 was decreased [46]. In muscle from the combined Grb10/Grb14-knockout mouse, marked decreases were observed in insulin-stimulated IRS1 phosphorylation [47].…”

Tissue-specific regulation and function of Grb10 during growth and neuronal commitment

“…Embryonic overgrowth also reflects the important role of Grb10 in placental development, with Grb10 deficiency resulting in increased placental size and efficiency (42). Postnatal overgrowth has been partially attributed to the increased lean mass observed in Grb10 deletion mice (37,38,43). Grb10 deletion mice have an increased number of muscle fibers and the molecular hallmarks of increased insulin signaling in muscle (44).…”

“…Notably, Grb10 overexpression is linked to severe pancreatic dysfunction and dysmorphia in juvenile mice (36). Reduction in Grb10 expression is associated with widespread neonatal and postnatal overgrowth, along with increased sensitivity to insulin (6,34,37,38). Pancreas-specific Grb10 deletion results in increased insulin production and improved glucose tolerance (39).…”