Title:
Systems biology of insulin action

Speaker:
Shinya Kuroda
Department of Biological Sciences, University of Tokyo

Abstract:
Insulin selectively regulates many metabolic functions, such as glycogenesis, gluconeogenesis and protein synthesis, through the AKT pathway depending on its temporal patterns, such as additional secretion, which is a pulse-like secretion in response to meals, and basal secretion, which is the low and constant secretion during fasting. We developed a simple computational model of the insulin-dependent AKT pathway, and found that the pathway uses “temporal patterns” for selective downstream regulation via differences in their network structures and kinetics (Kubota et al., Mol. Cell, 2012, Noguchi et al, Mol. Sys. Biol, 2013, Kubota et al, Cell Sys. 2018). Our results demonstrate that the AKT pathway can multiplex distinct patterns of insulin and the downstream molecules selectively decode the temporal patterns of insulin.
Insulin action involves dynamic molecular interactions between multiple layers including protein phosphorylation, and metabolites. We performed metabolomic and phospho-proteomic analysis in insulin-stimulated Fao hepatoma cells, and automatically reconstructed global molecular network of insulin action by use of trans “omics” data together with several databases. We found a landscape of global network of insulin-dependent metabolic control that involves 13 protein kinases, 26 phosphorylated metabolic enzymes, and 35 allosteric effectors, resulting in quantitative changes in 44 metabolites (Yugi et al, Cell Rep. 2014, Yugi et al, Trends. Biotech., 2016, Yugi ewt al, Curr. Opin. Sys. Biol., 2018). We also performed the transcriptomic analysis of insulin-dependent gene expression and found that selective regulation of up-regulated and down-regulated genes by temporal patterns and doses of insulin (Sano et al, Sci. Signal, 2016), and contracted insulin dose-dependent regulation of trans-omic network (Kawata et al, iScience, 2018, Genes Cells, 2019)