In the fed state, insulin stimulates glucose uptake into muscle and inhibits glucose output from liver via a signaling pathway that culminates in the activation of the Ser/Thr protein kinase PKB/Akt. We have recently identified a 358 amino acid Akt-interacting protein whose expression is stimulated 10-fold in liver under fasting compared to fed conditions. Based on its proposed function, the Akt- interacting protein has been named Fasting Inducible Negative Regulator (FINR). The overall goal of this proposal is to test the hypothesis that FINR is a negative signal that contributes to insulin resistance under chronic fasting conditions and in type II diabetes.
Three specific aims are proposed: I. We will characterize the mechanism by which FINR inhibits PKB/Akt activity, and we will characterize relevant interaction domains in each protein. II. We will characterize the mechanism by which FINR mRNA expression is induced under fasting conditions. The expression of a putative FINR alternative splice product that is unable to associate with Akt will also be investigated. III. We will characterize the role of FINR in hepatic glucose homeostasis by acute adenoviral infection and by developing transgenic mice that over-express FINR constitutively in liver and other insulin sensitive tissues like muscle. These studies should provide important insights into a novel regulator of glucose homeostasis.
| Altarejos, Judith Y; Montminy, Marc (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12:141-51 |
| Wang, Yiguo; Vera, Liliana; Fischer, Wolfgang H et al. (2009) The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature 460:534-7 |
| Qi, Ling; Heredia, Jose E; Altarejos, Judith Y et al. (2006) TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312:1763-6 |
