FOXC2 mRNA Expression and a 5' untranslated region polymorphism of the gene are associated with insulin resistance.
ABSTRACT 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.
SourceAvailable from: Sumi Surendran[Show abstract] [Hide abstract]
ABSTRACT: Chronic venous disease (CVD) is one of the most prevalent yet underrated disorders worldwide. High heritability estimates of CVD indicate prominent genetic components in its etiology and pathology. Mutations in human forkhead box C2 (FoxC2) gene are strongly associated with valve failure in saphenous and deep veins of lower extremities. We explored the association of genetic variants of FoxC2 as well as FoxC2 mRNA and protein expression levels with CVD of lower limbs. We systematically sequenced the single coding exon, 5' and 3' flanking regions of FoxC2 gene in 754 study subjects which includes 382 patients with CVD and 372 healthy subjects. Four novel and three reported polymorphisms were identified in our cohort. Three variants in 5' flanking region and one in 3' flanking region of FoxC2 gene were significantly associated with CVD risk. FoxC2 mRNA in vein tissues from 22 patients was 4±1.42 fold increased compared to saphenous veins from 20 normal subjects (p<0.01). FoxC2 protein was also significantly upregulated in varicose veins compared to control samples. The c.-512C>T (rs34221221: C>T) variant which is located in the FoxC2 putative promoter region was further analyzed. Functional analysis of c.-512C>T revealed increased mRNA and protein expression in patients with homozygous TT genotype compared to heterozygous CT and wild CC genotypes. Luciferase assay indicated higher transcriptional activity of mutant compared to wild genotype of this variant. These findings suggested that c.-512C>T variant of FoxC2 was strongly associated with susceptibility to CVD and also that this variant resulted in FoxC2 overexpression. To obtain a mechanistic insight into the role of upregulated FoxC2 in varicosities, we overexpressed FoxC2 in venous endothelial cells and observed elevated expression of arterial markers Dll4 and Hey2 and downregulation of venous marker COUP-TFII. Our study indicates altered FoxC2-Notch signaling in saphenous vein wall remodeling in patients with varicose veins.PLoS ONE 03/2014; 9(3):e90682. DOI:10.1371/journal.pone.0090682 · 3.53 Impact Factor
Article: On the generators of SP n ( Z )[Show abstract] [Hide abstract]
ABSTRACT: We give a short variant of the classical proofs for the generation of the symplectic group Spn(Z) over Z by the standard matrices.Linear Algebra and its Applications 01/1997; 253(1):363-367. DOI:10.1016/0024-3795(95)00708-3 · 0.98 Impact Factor
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ABSTRACT: The molecular mechanism to regulate energy balance is not completely understood. Here we observed that Egr-1 expression in white adipose tissue (WAT) was highly correlated with dietary-induced obesity and insulin resistance both in mice and humans. Egr-1 null mice were protected from diet-induced obesity and obesity-associated pathologies such as fatty liver, insulin resistance, hyperlipidemia and hyperinsulinemia. This phenotype can be largely explained by the increase of energy expenditure in Egr-1 null mice. Characterization of these mice revealed that the expression of FOXC2 and its target genes were significantly elevated in white adipose tissues, leading to WAT energy expenditure instead of energy storage. Altogether, these studies suggest an important role for Egr-1, which, by repressing FOXC2 expression, promotes energy storage in WAT and favored the development of obesity under high energy intake.Scientific Reports 03/2013; 3:1476. DOI:10.1038/srep01476 · 5.08 Impact Factor