FOXC2 mRNA Expression and a 5' untranslated region polymorphism of the gene are associated with insulin resistance.
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.
Ridderstråle
Martin
M
Department of Endocrinology, Lund University, Wallenberg Laboratory, University Hospital Malmö, S-205 02 Malmö, Sweden. martin.ridderstrale@endo.mas.lu.se
Carlsson
Emma
E
Klannemark
Mia
M
Cederberg
Anna
A
Kösters
Christina
C
Tornqvist
Hans
H
Storgaard
Heidi
H
Vaag
Allan
A
Enerbäck
Sven
S
Groop
Leif
L
D020121:5' Untranslated Regions / Q000235:genetics*; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D040521:Subcutaneous Tissue / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D014781:Viscera / Q000378:metabolism
D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D012333:RNA, Messenger; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein