The role of ATF2 in insulin action

Abstract

We have identified ATF2 as a component of the cellular and in vivo insulin signaling systems. Insulin induced ATF2-phosphorylation in A14 fibroblasts, 3T3L1-adipocytes and several mouse tissues in vivo. In cell lines, the insulin-induced ATF2-phosphorylation was dependent on cooperation between two Ras-dependent MAPK-pathways: ERK and p38/JNK. Analysis of several described ATF2-target genes identified insulin-induced expression of Egr1, ATF3, c-jun and SREBP1c as being ATF2-dependent in cell lines. These genes encode transcription factors whose targets have been postulated to be involved in several aspects of normal insulin action, like control of hepatic fat and glucose metabolism and proliferation and differentiation of beta-cells. Quantitative PCR analysis showed increased mRNA expression of these genes in mouse livers correlating with hepatic ATF2-phosphorylation induced by insulin, but also in response to HFD-induced insulin resistance. In addition, the known ATF2 target genes, the inflammatory cytokines IL1-beta and TNF-alpha were also significantly induced by the HFD in liver. Although the elucidation of the exact role of ATF2 activation under these conditions needs further experimentation, the data presented in this thesis suggest a potential dual function for ATF2 as a mediator of insulin action on the one hand and a putative regulator of the development or maintenance of insulin resistance and/or diabetes-associated complications on the other.