title: 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, with the antidiabetes action of metformin being thought to be achieved at least in part through suppression of gluconeogenesis.
  
  
  METHODS
  We investigated whether the transcription factor KLF15 has a role 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 peroxisome proliferator-activated receptor gamma coactivator 1alpha. Liver-specific ablation of KLF15 in diabetic mice resulted in downregulation of the expression of genes for gluconeogenic or amino acid catabolic enzymes and in amelioration of hyperglycemia. Exposure of cultured hepatocytes to metformin reduced the abundance of KLF15 through acceleration of its degradation and downregulation 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, 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 downregulation of KLF15 and consequent attenuation of the expression of such genes.
authors.affiliation: Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Takashima
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakaue
authors.forename: Yu
authors.initials: Y
authors.lastname: Wataoka
authors.forename: Aki
authors.initials: A
authors.lastname: Emi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Senga
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuki
authors.forename: Eijiro
authors.initials: E
authors.lastname: Watanabe
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hiramatsu
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; C520013:Klf15 protein, rat; D051741:Kruppel-Like Transcription Factors; D008687:Metformin
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