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.
Address correspondence and reprint requests to Dr. Martin Ridderstråle, Department of Endocrinology, Lund University, Wallenberg Laboratory, University Hospital Malmö, S-205 02 Malmö, Sweden. E-mail:.
Received for publication 6 June 2002 and accepted in revised form 26 August 2002.
α-FOXC2, anti-FOXC2; HOMA-IR, homeostasis model assessment of insulin resistance; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; OSD, observed sum of differences; RMR, resting metabolic rate; SAT, subcutaneous adipose tissue; SSCP, single-strand conformational polymorphism; VAT, visceral adipose tissue; WHR, waist-hip-ratio.