The Adipocyte-Expressed Forkhead Transcription Factor Foxc2 Regulates Metabolism Through Altered Mitochondrial Function
- Martin E. Lidell1,
- Erin L. Seifert2,
- Rickard Westergren1,
- Mikael Heglind1,
- Adrienne Gowing2,
- Valentina Sukonina1,
- Zahra Arani1,
- Paula Itkonen3,
- Simonetta Wallin4,
- Fredrik Westberg4,
- Julia Fernandez-Rodriguez1,
- Markku Laakso3,
- Tommy Nilsson1,
- Xiao-Rong Peng4,
- Mary-Ellen Harper2 and
- Sven Enerbäck1
- 1Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- 2Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
- 3Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
- 4Bioscience Department, AstraZeneca RD, Mölndal, Sweden
- Corresponding author: Sven Enerbäck, .
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.
RESEARCH DESIGN AND 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-0409/-/DC1.
- Received March 25, 2010.
- Accepted November 18, 2010.
- © 2011 by the American Diabetes Association.
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