Obesity and type 2 diabetes are expanding rapidly and become a wide world health issue. These metabolic diseases are tightly associated with an insulin resistance state. Among insulin target tissues, liver plays a central role in the regulation of glucose homeostasis.
Insulin action is initiated by its binding to its receptors (IR) which, once activated, phosphorylate intracellular substrates and lead to the activation of transduction pathways implicating the kinase Akt and the transcription factor SREBP-1c. The molecular adapter Grb14, which is highly expressed in the liver, binds to the insulin-stimulated IR and inhibits its tyrosine kinase activity. However, the physiological role of Grb14 in liver metabolism was unexplored. In this study, we used RNA interference to investigate the consequences of Grb14 decrease on insulin-regulated intracellular signaling and on glucose and lipid metabolism in mouse primary cultured hepatocytes.
In Grb14-depleted hepatocytes, insulin-induced phosphorylation of Akt, and of its substrates GSK3 and Foxo1, were increased. These effects on insulin signaling are in agreement with the selective inhibitory effect of Grb14 on the receptor kinase. However, the metabolic and genic effects of insulin were differentially regulated after Grb14 down-regulation. Indeed, the insulin-mediated inhibition of hepatic glucose production and gluconeogenic gene expression was preserved. Surprisingly, despite the improved Akt pathway, the induction by insulin of SREBP-1c maturation was totally blunted. As a result, in the absence of Grb14, glycogen synthesis as well as glycolytic and lipogenic gene expression were not responsive to the stimulatory effect of insulin. This study provides evidence that Grb14 exerts a dual role on the regulation by insulin of hepatic metabolism: it inhibits IR catalytic activity, and acts also at a more distal step, i.e. SREBP-1c maturation, which effect is predominant under short-term inhibition of Grb14 expression.
03 - 07 May 2008
European Society of Endocrinology