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Insulin, the most important hormone regulating glucose and lipid homeostasis in the body, triggers the intracellular protein kinases and activates or inactivates the hormone-responsive gene transcriptional profiles that integrate to the metabolic pathway and maintain a steady level of blood glucose and lipids.Insulin receptor substrate protein-1 and -2 (IRS-1 & IRS-2) are the major mediators of insulin signaling that activate the PI-3Kinase and protein kinase B (Akt) and then suppress O-class of forkhead transcription factor Foxo1 by phosphorylating the Serine 253 in Foxo1.Recently we used the Cre/LoxP genetic approach to delete Foxo 1 in the liver of mice and our studies indicated that the liver deficient in Foxo 1 gene elevates expression levels of lipogenic genes, while inhibits gluconeogenic gene expression and impairs hepatic nutrient homeostasis (Zhang KB etc.Endocrinology, 153(2): 631-646, 2012).Since phosphorylation of Foxo 1 at the Serine 253 via the activation of PI3K/Akt in insulin signaling cascade promotes Foxo1 nuclear export and ubiquitylation, mediating the effect of insulin on gene expression and cellular function in metabolic regulation.To determine whether Foxo 1 at Ser253 regulates Foxo 1 activity, insulin resistance and nutrient homeostasis in vivo, we generated Foxo1 gene targeting vector in which Ser253 was replaced with alanine (A) to block insulinmediated phosphorylation and transfected the embryonic stem (ES) cells.A positive ES clone was obtained for mouse generation (Foxo1-S253A mice).The homozygous Foxo1-S253A/A mice displayed normal body weight, increased postprandial blood glucose concentrations, elevated blood insulin and leptin concentrations, reduced blood triglyceride levels, and developed insulin resistance.Thus, we firstly demonstrated that a blockage of Fox o 1 at Ser253 phosphorylation is sufficient to cause dysregulation in metabolism and nutrient homeostasis in vivo.