A novel polymorphism in the proximal UCP3 promoter region: effect on skeletal muscle UCP3 mRNA expression and obesity in male non-diabetic Pima Indians.
OBJECTIVE
UCP2 and UCP3 are newly discovered uncoupling proteins, which are thought to underlie the variability in energy metabolism in humans. Mutations in the UCP2 and/or UCP3 gene have been associated with sleeping metabolic rate. Recently we reported that skeletal muscle UCP3 mRNA expression was positively correlated with sleeping metabolic rate in Pima Indians. To study whether genetic variation in the promoter region of UCP3 contributed to the variation in expression of UCP3, we screened part of the proximal promoter region for polymorphisms.


METHODS
In the first part of the study, the proximal promoter region of UCP3 was screened by direct sequencing in 24 non-diabetic Pima Indians (range body mass index (BMI): 18-47 kg/m2) (Schrauwen et al. Diabetes 1999; 48: 146-149) and skeletal muscle UCP3 mRNA expression was measured by RT-PCR. In the second part of the study, we typed the polymorphism found in the first part of the study in 67 Pima Indians (32 males, 35 females) from the upper and lower extremes of the BMI distribution.


RESULTS
We identified a novel C to T substitution in the UCP3 promoter, 6bp upstream of the putative TATA signal, and 55bp upstream of the transcription starting site. Among 18 male subjects, skeletal muscle UCP3 mRNA expression was significantly higher in the C/T & T/T group compared to the C/C homozygotes (P<0.02). However, in the group of 67 Pima Indians genotype frequencies were not different in the obese and lean groups.


CONCLUSIONS
We identified a novel polymorphism in the proximal promoter region of UCP3, which was associated with increased skeletal muscle expression of UCP3 in male non-diabetic Pima Indians. Considering the suggested role of UCP3 in energy metabolism, this polymorphism might be of physiological importance in the regulation of energy balance.
Schrauwen
P
P
Department of Human Biology, Maastricht University, The Netherlands.
Xia
J
J
Walder
K
K
Snitker
S
S
Ravussin
E
E
D019943:Amino Acid Substitution; D001130:Arizona; D044466:Asian People / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007473:Ion Channels; D008297:Male; D024101:Mitochondrial Proteins; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000502:physiology*; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D017931:DNA Primers; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3