Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians

Abstract

The UCP2-UCP3 gene cluster maps to chromosome 11q13 in humans, and polymorphisms in these genes may contribute to obesity through effects on energy metabolism. DNA sequencing of UCP2 and UCP3 revealed three polymorphisms informative for association studies: an Ala-->Val substitution in exon 4 of UCP2, a 45 bp insertion/deletion in the 3'-untranslated region of exon 8 of UCP2 and a C-->T silent polymorphism in exon 3 of UCP3. Initially, 82 young (mean age = 30 +/- 7 years), unrelated, full-blooded, non-diabetic Pima Indians were typed for these polymorphisms by direct sequencing. The three sites were in linkage disequilibrium ( P < 0.00001). The UCP2 variants were associated with metabolic rate during sleep (exon 4, P = 0.007; exon 8, P = 0.016) and over 24 h (exon 8, P = 0.038). Heterozygotes for UCP2 variants had higher metabolic rates than homozygotes. The UCP3 variant was not significantly associated with metabolic rate or obesity. In a further 790 full-blooded Pima Indians, there was no significant association between the insertion/deletion polymorphism and body mass index (BMI). However, when only individuals >45 years of age were considered, heterozygotes (subjects with the highest sleeping metabolic rate) had the lowest BMI (P = 0.04). The location of the insertion/deletion polymorphism suggested a role in mRNA stability; however, it appeared to have no effect on skeletal muscle UCP2 mRNA levels in a subset of 23 randomly chosen Pima Indians. In conclusion, these results suggest a contribution from UCP2 (or UCP3) to variation in metabolic rate in young Pima Indians which may contribute to overall body fat content later in life.

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 humans, some, but not all (Klannemark et al 1998), studies showed that UCP2 gene variants are implicated in diabetes, obesity, and fat metabolism (Zhang et al 2001) and are strongly linked to resting energy expenditure (Astrup et al 1999;Buemann et al 2001;Walder et al 1998).…”

“…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).…”

Putative role of polymorphisms in UCP1-3 genes for diabetic nephropathy

“…G (À 3862) polymorphism in the promoter of the UCP1 gene has been associated with increased BMI (Hayakawa et al, 1999;Heilbronn et al, 2000) whereas other studies have failed to demonstrate any association between obesity and this UCP1 polymorphism (Gagnon et al, 1998;Urhammer et al, 1997). The I/D variant of UCP2 in the 3 0 untranslated region of exon 8 of UCP2 was found to be associated with increased sleeping metabolic rate and 24-h energy expenditure and with lower BMI in Pima Indians (Walder et al, 1998), and homozygous carriers of the insertion had increased BMI in a South Indian population (Cassell et al, 1999). The T allele in UCP3 C !…”

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

“…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. 10 In addition, UCP2 is at least in part regulated through PPARg as PPARg agonists increases adipose UCP2 expression.…”

“…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.…”