Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action.
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.
Takashima
Mototsugu
M
Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan.
Ogawa
Wataru
W
Hayashi
Kumiko
K
Inoue
Hiroshi
H
Kinoshita
Shinichi
S
Okamoto
Yasuo
Y
Sakaue
Hiroshi
H
Wataoka
Yu
Y
Emi
Aki
A
Senga
Yoko
Y
Matsuki
Yasushi
Y
Watanabe
Eijiro
E
Hiramatsu
Ryuji
R
Kasuga
Masato
M
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
D001786:Blood Glucose; D007004:Hypoglycemic Agents; C520013:Klf15 protein, rat; D051741:Kruppel-Like Transcription Factors; D008687:Metformin
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