Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis.

摘要: The livers of insulin-resistant, diabetic mice manifest selective insulin resistance, suggesting a bifurcation in the signaling pathway: Insulin loses its ability to block glucose production (i.e., it fails suppress PEPCK and other genes gluconeogenesis), yet retains stimulate fatty acid synthesis continued enhancement lipogenesis). Enhanced lipogenesis is accompanied by an insulin-stimulated increase mRNA encoding SREBP-1c, transcription factor that activates entire lipogenic program. Here, we report branch point pathway may account for resistance. Exposure rat hepatocytes produced 25-fold SREBP-1c 95% decrease mRNA. Insulin-mediated changes both mRNAs were blocked inhibitors PI3K Akt, indicating these kinases are required pathways. In contrast, subnanomolar concentrations rapamycin, inhibitor mTORC1 kinase, induction but had no effect on suppression PEPCK. We observed similar rapamycin rats experienced surge response fasting-refeeding protocol. A specific S6 downstream target mTORC1, did not distinct from kinase. These results establish as essential component insulin-regulated hepatic gluconeogenesis, help resolve paradox resistance rodents.