FOXC2 mRNA Expression and a 5' Untranslated Region Polymorphism of the Gene Are Associated With Insulin Resistance

University of Gothenburg, Goeteborg, Västra Götaland, Sweden
Diabetes (Impact Factor: 8.1). 01/2003; 51(12):3554-60. DOI: 10.2337/diabetes.51.12.3554
Source: PubMed


The human transcription factor FOXC2 has recently been shown to protect against diet-induced insulin resistance in transgenic mice. We investigated the expression of FOXC2 in fat and muscle and performed a genetic analysis in human subjects. FOXC2 mRNA levels were increased in visceral compared with subcutaneous fat from obese subjects (12 +/- 4-fold; P = 0.0001), and there was a correlation between whole-body insulin sensitivity and FOXC2 mRNA levels in visceral fat (fS-insulin R = -0.64, P = 0.01, and homeostasis model assessment of insulin resistance [HOMA-IR] R = -0.68, P = 0.007) and skeletal muscle (fS-insulin R = -0.57, P = 0.03, and HOMA-IR R = -0.55, P = 0.04). Mutation screening of the FOXC2 gene identified a common polymorphism in the 5' untranslated region (C-512T). The T allele was associated with enhanced insulin sensitivity (HOMA-IR P = 0.007) and lower plasma triglyceride levels in females (P = 0.007). Also, the higher expression of FOXC2 in visceral than in subcutaneous fat was restricted to subjects homozygous for the T allele (P = 0.03 vs. P = 0.7). Our data suggest that increased FOXC2 expression may protect against insulin resistance in human subjects and that genetic variability in the gene may influence features associated with the metabolic syndrome.

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    • "FOXC2 is a member of forkhead transcription factors and normally expressed only in adipose tissue. FOXC2 promoter polymorphism and abnormal expression had been shown associated with obesity and insulin resistance26272829. Overexpression of FOXC2 in adipose tissue causes a profound gene expression change including β-adrenergic receptors, PPARs and PGC-1, and BAT-specific gene UCP1 in WAT depot, which drives WAT depot to acquire a brown fat-like histology and to dissipate energy rather than to store energy203031. "
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    • "This is interesting since there is growing evidence that reduction in mitochondrial fusion is an important etiological factor in development of obesity and insulin resistance (1,14,15). Based on previous findings demonstrating that Foxc2 is upregulated in response to insulin (16) and high-caloric diet (13) and on results presented herein, we propose that Foxc2 is crucial in a metabolically regulated gene circuit, allowing the adipocyte to adapt to alterations in systemic substrate availability. "
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    ABSTRACT: 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. 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. 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. 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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