A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans

Abstract

Obesity is the most common nutritional disorder in Western society. Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue. Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis and is therefore a candidate gene for obesity. We show here that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant reduction in obesity prevalence associated with the less-common allele. We confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area. Despite its modest effect, but because of its high frequency (approximately 63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.

Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases

“…It was reported earlier to alter mRNA expression of UCP2 in vivo and in vitro,with the common G allele being associated with lower mRNA expression levels. 4,7,8 High expression of UCP2 has been reported in cells of the immune system, and the expression was affected by the -866 G variation in vivo and in vitro. 4,9,10 The -866 G allele decreasing the UCP2 expression is associated with increased risk to chronic inflammatory diseases.…”

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

“…In particular, VV genotype, in comparison to those who have the AA or A/V genotype, have a lower degree of uncoupling, lower energy expenditure (Astrup et al 1999), higher exercise energy efficiency (Buemann et al 2001), and lower fat oxidation. However, it has been reported that persons with the I/D genotype have an increased basal metabolic rate, increased 24-h energy expenditure and decreased BMI (Esterbauer et al 2001), as well as a low deposition index (Walder et al 1998).Recently, the −866 G-allele has been described to influence UCP2 transcription, to be associated with reduced adipose tissue mRNA expression, reduced transcriptional activity in vitro and in vivo, high BMI, fat mass changes (Yoon et al 2007), increased risk of obesity (Esterbauer et al 2001;Argyropoulos and Harper 2002;Vogler et al 2005), increased insulin response to glucose and reduced risk of T2D (Krempler et al 2002;Esterbauer et al 2001;Sesti et al 2003).…”

PPARγ activity in subcutaneous abdominal fat tissue and fat mass gain during short-term overfeeding

“…The study enclosed a 7-day baseline period (days 1-8) and a 14-day overfeeding period (days [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. During the baseline period subjects chose their diets from a variety of food items provided daily in weighed food packages, bringing back the leftovers the next day, for calculation of habitual energy intake.…”

“…The expression of UCP2 is reduced in adipose tissue of obese vs lean subjects. 12 In a population-based sample from the same geographic area, a common UCP2 polymorphism could account for 15% of the obesity prevalence, 12 and genetic variation at the UCP2 locus is associated with energy expenditure in Pima Indians. 21 Together, these observations suggest a role for UCP2 in obesity by influencing energy metabolism although a specific uncoupling function has not been confirmed in humans.…”

“…7,8 In addition, PPARg is involved in the regulation of the uncoupling protein 2 (UCP2) as PPARg agonists are shown to increase UCP2 expression in adipose tissue. [9][10][11] UCP2 mRNA levels are reduced in adipose tissue from obese compared to lean persons, 12 which suggests a role for UCP2 in obesity by influencing energy metabolism although a specific uncoupling function has not been confirmed in humans. 10 We investigated whether UCP2 influences fat gain during overfeeding.…”