Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action

Abstract Objective– An increase in the rate of gluconeogenesis is largely responsible for the hyperglycemia in individuals with type 2 diabetes mellitus, with the antidiabetes action of metformin being thought to be achieved at least in part through suppression of gluconeogenesis. Research design and methods– We investigated the possible role of the transcription factor KLF15 in the regulation of gluconeogenesis and whether KLF15 participates in the antidiabetes effect of metformin. Results– Here we show that KLF15 regulates the expression of genes for gluconeogenic or amino acid–degrading enzymes in coordination with the transcriptional coactivator PGC1α. Liver-specific ablation of KLF15 in diabetic mice resulted in down-regulation of the expression of genes for gluconeogenic or amino acid catabolic enzymes as well as in amelioration of hyperglycemia. Exposure of cultured hepatocytes to metformin reduced the abundance of KLF15 through acceleration of its degradation and down-regulation of its mRNA. Metformin suppressed the expression of genes for gluconeogenic or amino acid–degrading enzymes in cultured hepatocytes, and these effects of metformin were attenuated by restoration of KLF15 expression. Administration of metformin to mice inhibited both the expression of KLF15 and glucose production in the liver, with the latter effect also being attenuated by restoration of hepatic KLF15 expression. Conclusions– KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid–degrading enzymes, and that the inhibitory effect of metformin on gluconeogenesis is mediated at least in part by down-regulation of KLF15 and consequent attenuation of the expression of such genes.