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The Adipocyte-Expressed Forkhead Transcription Factor Foxc2 Regulates Metabolism Through Altered Mitochondrial Function

Journal article
Authors Martin Lidell
EL Seifert
Rickard Westergren
Mikael Heglind
A Gowing
Valentina Sukonina
Zahra Arani
P Itkonen
S Wallin
F Westberg
Julia Fernandez-Rodriguez
M Laakso
Tommy Nilsson
XR Peng
ME Harper
Sven Enerbäck
Published in Diabetes
Volume 60
Issue 2
Pages 427-435
ISSN 0012-1797
Publication year 2011
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Pages 427-435
Language en
Links dx.doi.org/10.2337/db10-0409
Subject categories Medical Genetics, Endocrinology and Diabetes

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. 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.

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