A novel polymorphism in the proximal UCP3 promoter region: effect on skeletal muscle UCP3 mRNA expression and obesity in male nondiabetic Pima Indians

OBJECTIVE: UCP2 and UCP3 are newly discovered uncoupling proteins, which ar e thought to underlie the variability in energy metabolism in humans. Mutat ions in the UCP2 and/or UCP3 gene have been associated with sleeping metabo lic rate. Recently we reported that skeletal muscle UCP3 mRNA expression wa s positively correlated with sleeping metabolic rate in Pima Indians. To st udy whether genetic variation in the promoter region of UCP3 contributed to the variation in expression of UCP3, we screened part of the proximal prom oter region for polymorphisms. METHODS: In the first part of the study, the proximal promoter region of UC P3 was screened by direct sequencing in 24 non-diabetic Pima Indians (range body mass index (BMI): 18- 47 kg/m(2)) (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 fi rst part of the study in 67 Pima Indians (32 males, 35 females) from the up per and lower extremes of the BMI distribution. RESULTS: We identified a novel C to T substitution in the UCP3 promoter, 6b p upstream of the putative TATA signal, and 55bp upstream of the transcript ion starting site, Among 18 male subjects, skeletal muscle UCP3 mRNA expres sion was significantly higher in the C/T & T/T group compared to the C/C ho mozygotes (P < 0.02). However, in the group of 67 Pima Indians genotype fre quencies were not different in the obese and lean groups. CONCLUSION: We identified a novel polymorphism in the proximal promoter reg ion 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 i mportance in the regulation of energy balance.