Functional analysis of hepatic FOXO3 signalling in glucose and lipid metabolism

In the present study we demonstrate that constitutive activation of FoxO3 results in impaired glucose and lipid metabolism in transgenic mice. FoxO3 activation resulted in impaired glucose tolerance due to upregulation of gluconeogenic target genes followed by hyperinsulinemia and impaired insulin sensitivity. Moreover expression of constitutively active FoxO3 results in activation of catabolic pathways including glycogenolysis and lipid catabolic pathways in the liver. On the other hand FoxO3 inhibits lipid synthesis pathways. Consistently our gene expression analysis has identified several genes important for regulation of glucose and lipid catabolic pathways as reported in type 2 diabetes conditions. However the disease progression in transgenic mice resulted in hypoglycemia might be as a consequence of beginning of liver failure, hyperinsulinemia and pancreatic hyperplasia. Strikingly the administration of metformin rapidly and completely normalizes glucose, insulin as well as lipid metabolism in mice expressing constitutively active FoxO3 (Figure 42). Our findings identify FoxO3 as a critical metabolic regulator and a potential hepatic target of metformin. Taken together the results obtained from constitutive activation of FoxO3 in the liver imply that dysbalanced FoxO3 activity in the liver augments insulin resistance and type 2 diabetes. Therefore tight regulation of FoxO3 activity would be very crucial and agents controlling hepatic FoxO3 system may represent therapeutic tools to prevent type 2 diabetes.