title: The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function.
abstract: OBJECTIVE
  Previous findings demonstrate that enhanced expression of the forkhead transcription factor Foxc2 in adipose tissue leads to a lean and insulin-sensitive phenotype. These findings prompted us to further investigate the role of Foxc2 in the regulation of genes of fundamental importance for metabolism and mitochondrial function.
  
  
  METHODS
  The effects of Foxc2 on expression of genes involved in mitochondriogenesis and mitochondrial function were assessed by quantitative real-time PCR. The potential of a direct transcriptional regulation of regulated genes was tested in promoter assays, and mitochondrial morphology was investigated by electron microscopy. Mitochondrial function was tested by measuring oxygen consumption and extracellular acidification rates as well as palmitate oxidation.
  
  
  RESULTS
  Enhanced expression of FOXC2 in adipocytes or in cells with no endogenous Foxc2 expression induces mitochondriogenesis and an elongated mitochondrial morphology. Together with increased aerobic metabolic capacity, increased palmitate oxidation, and upregulation of genes encoding respiratory complexes and of brown fat-related genes, Foxc2 also specifically induces mitochondrial fusion genes in adipocytes. Among tested forkhead genes, Foxc2 is unique in its ability to trans-activate the nuclear-encoded mitochondrial transcription factor A (mtTFA/Tfam) gene--a master regulator of mitochondrial biogenesis. In human adipose tissue the expression levels of mtTFA/Tfam and of fusion genes also correlate with that of Foxc2.
  
  
  CONCLUSIONS
  We previously showed that a high-calorie diet and insulin induce Foxc2 in adipocytes; the current findings identify a previously unknown role for Foxc2 as an important metabo-regulator of mitochondrial morphology and metabolism.
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Lidell
authors.forename: Erin L
authors.initials: EL
authors.lastname: Seifert
authors.forename: Rickard
authors.initials: R
authors.lastname: Westergren
authors.forename: Mikael
authors.initials: M
authors.lastname: Heglind
authors.forename: Adrienne
authors.initials: A
authors.lastname: Gowing
authors.forename: Valentina
authors.initials: V
authors.lastname: Sukonina
authors.forename: Zahra
authors.initials: Z
authors.lastname: Arani
authors.forename: Paula
authors.initials: P
authors.lastname: Itkonen
authors.forename: Simonetta
authors.initials: S
authors.lastname: Wallin
authors.forename: Fredrik
authors.initials: F
authors.lastname: Westberg
authors.forename: Julia
authors.initials: J
authors.lastname: Fernandez-Rodriguez
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Tommy
authors.initials: T
authors.lastname: Nilsson
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Peng
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.forename: Sven
authors.initials: S
authors.lastname: Enerbäck
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000494:pharmacology; D014162:Transfection
chemical_list: D005227:Fatty Acids; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D007328:Insulin; D012265:Ribonucleotides; C082078:mesenchyme fork head 1 protein; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide