title: Metformin induces PGC-1α expression and selectively affects hepatic PGC-1α functions.
abstract: OBJECTIVE
  The objective of this study was to determine how the AMPK activating antidiabetic drug metformin affects the major activator of hepatic gluconeogenesis, PPARγ coactivator 1α (PGC-1α) and liver functions regulated by PGC-1α.
  
  
  METHODS
  Mouse and human primary hepatocytes and mice in vivo were treated with metformin. Adenoviral overexpression, siRNA and reporter gene constructs were used for mechanistic studies.
  
  
  RESULTS
  Metformin increased PGC-1α mRNA and protein expression in mouse primary hepatocytes. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) (another AMPK activator) had the opposite effect. Metformin also increased PGC-1α in human primary hepatocytes; this effect of metformin was abolished by AMPK inhibitor compound C and sirtuin 1 siRNA. AMPK overexpression by AMPK-Ad also increased PGC-1α. Whereas metformin increased PGC-1α, it down-regulated gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Furthermore, metformin attenuated the increase in PEPCK and G6Pase mRNAs induced by PGC-1α overexpression, but did not affect PGC-1α-mediated induction of mitochondrial genes. Metformin down-regulated several key transcription factors that mediate the effect of PGC-1α on gluconeogenic genes including Krüppel-like factor 15, forkhead box protein O1 and hepatocyte NF 4α, whereas it increased nuclear respiratory factor 1, which is involved in PGC-1α-mediated regulation of mitochondrial proteins.
  
  
  CONCLUSIONS
  Down-regulation of PGC-1α is not necessary for suppression of gluconeogenic genes by metformin. Importantly, metformin selectively affects hepatic PGC-1α-mediated gene regulation and prevents activation of gluconeogenesis, but does not influence its regulation of mitochondrial genes. These results identify selective modulation of hepatic PGC-1α functions as a novel mechanism involved in the therapeutic action of metformin.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Sanna-Mari
authors.initials: SM
authors.lastname: Aatsinki
authors.forename: Marcin
authors.initials: M
authors.lastname: Buler
authors.forename: Henriikka
authors.initials: H
authors.lastname: Salomäki
authors.forename: Markku
authors.initials: M
authors.lastname: Koulu
authors.forename: Petr
authors.initials: P
authors.lastname: Pavek
authors.forename: Jukka
authors.initials: J
authors.lastname: Hakkola
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D007004:Hypoglycemic Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D008687:Metformin
keywords: AMPK; G6Pase; PEPCK; PGC-1α; SIRT1; gluconeogenesis; liver; metformin