Consequences of the modification of Grb14 expression level on adipocyte differentiation and metabolism
Diana Goenaga1, Marthe Moldes1, Lowena Holt2, Roger Daly2, Jean Girard1 & Anne-Françoise Burnol1
Grb14 is a molecular adaptor that inhibits insulin signaling by interacting with the activated insulin receptor and inhibiting its tyrosine kinase activity. In various models of insulin resistance, including obese mice and type 2 diabetes patients, an inverse correlation was reported between Grb14 expression in adipose tissue and insulin sensitivity. To elucidate Grb14 function in this specific tissue, we studied the impact of modifications of Grb14 level of expression on adipocyte metabolism and differentiation.
We established a 3T3-L1 cell line with an inducible over expression of Grb14 and we studied at the same time embryonic fibroblasts obtained from Grb14−/− mice (MEF KO). Adipose differentiation, insulin signaling and adipokiness production and secretion have been observed in these two cell lines.
We demonstrate that adipose differentiation is not altered by Grb14 over expression. However, MEF KO lacking Grb14 show an increase both in cell proliferation and in adipose differentiation. Grb14 over expression leads to an inhibition of Akt and ERK1/2 insulin stimulated phosphorylation and its absence in the MEF KO enhances these same signaling events. Despite this effect on early insulin signaling, alteration of Grb14 expression level does not modify insulin induced glucose transport in both cell lines. Concerning the endocrine capacities of these adipocytes, we observe a 50% decrease in leptin secretion when Grb14 is overexpressed. On the other hand, adiponectin production and secretion are not altered by Grb14 expression level variations.
These experiments bring new knowledge about Grb14 function in adipose tissue, both on the metabolic and the endocrine aspects. Furthermore, they suggest that beyond it is role as an inhibitor of insulin signaling, Grb14 seems to act on other major cellular functions such as cell proliferation and adipose differentiation.