Insulin action in the brain : intracellular signaling and FoxO transcription factors

Abstract

Insulin in the central nervous system affects processes that involve learning and memory, synaptic plasticity and neuronal survival. However, the mechanism by which insulin affects these processes is unclear. In addition, the mechanism underlying the negative influence of hyperinsulinemia in the pathology of disease is also not known. The aim of this thesis was to explore how insulin modulates intracellular signaling routes and how these routes relate to long lasting changes in synaptic plasticity. In chapter 2, the intracellular routes activated in response to insulin in cells of neuronal origin were investigated. In addition to this, the effect of insulin on intracellular crosstalk between kinases was studied. Since insulin has been described to have both beneficial and negative effects related to the period of insulin administration (see above), short- and long-term insulin treatment and its effects on the activation of signaling routes were investigated.

Since insulin has been shown to have an effect on synaptic plasticity, the effect of insulin on synaptic plasticity in the hippocampus was investigated (chapter 3). Additionally, a signal transduction route which functions as a mediator of insulin signaling we described in chapter 2 was studied.In chapter 4, a review of the literature on FoxO proteins and their regulation by insulin and insulin like factors is provided. The upstream signaling components which regulate FoxO proteins and the transcriptional mechanism regulating FoxO target genes and function are described. Finally, the in vivo relevance of FoxO factors in regulating metabolism and homeostasis is discussed. In chapter 5, the identification of FoxO6 from brain tissue, a novel member of the FoxO subgroup of forkhead transcription factors which serves as a transcriptional end-point of insulin signaling is described. In chapter 6, the intra-molecular mechanisms underlying FoxO6 function are described to gain more insight into how insulin or other growth factors influence the activity of FoxO6. In chapter 7, the results obtained are summarized and their relevance for insulin signaling, neuronal metabolism and survival is discussed.