An uncoupling protein 2 gene variant is associated with a raised body mass index but not Type II diabetes

Abstract

The regulation of body fat equilibrium in mammals depends on a balance between diet and energy expenditure. Energy expenditure occurs as a result of a combination of resting metabolic rate, physical exercise and non-shivering thermogenesis. It has become increasingly evident that even small calorific inequalities can lead to an increase in fat storage and obesity. There is also an intimate association between increasing body weight and Type II (non-insulin-dependent) diabetes even in populations in which obesity is not a common problem. The recent addition of two new uncoupling proteins (UCP), UCP2 and UCP3 to the mitochondrial carrier protein family of genes provides new opportunities to study thermogenesis in humans [1±3]. Activated uncoupling proteins promote proton transport and consequently decrease the proton electrochemical potential gradient across the inner mitochondrial membrane. This uncouples oxidative phosphorylation of ADP to ATP, leading to generation of heat [4]. A close relation between obesity in mice Diabetologia (1999) AbstractAims/hypothesis. Linkage between markers close to the uncoupling protein 2 and 3 genes (11q13) and resting metabolic rate and a pre-diabetic phenotype have been found. The syntenic region in mouse has been found to be linked to quantitative traits associated with obesity and diabetes. UCP2 and UCP3 could therefore have an important role in body weight regulation and susceptibility to diabetes. We investigated a recently identified variant of the UCP2 gene in exon 8 as a marker for glucose and weight homeostasis. Methods. Length variation of the UCP2 exon 8 variant was studied by the polymerase chain reaction and agarose gel electrophoresis. Sequence variants of the UCP3 gene were sought by semi-automated DNA sequencing. Results. In 453 South Indian subjects, we found an association in women between the UCP2 exon variant and body mass index (p = 0.018). These findings were replicated in a separate group of South Indian subjects (n = 143, p < 0.001) irrespective of sex. Although no association was found between the UCP2 exon 8 variant and overt obesity in British subjects, the UCP2 genotype of obese women (n = 83) correlated with fasting serum leptin concentration (p = 0.006) in the presence of extreme obesity. These observations could not be explained by tight linkage disequilibrium with a coding region variant in the region of the UCP3 gene of biological significance. Lastly, no association was found between UCP2 and Type II (non-insulin-dependent) diabetes using either a family based design (85 families) or case control study (normal glucose tolerance n = 335, impaired glucose tolerance n = 42, Type II diabetes n = 76). Conclusion/interpretation. We have described a UCP2 gene exon 8 variant that may affect susceptibility to weight gain by influencing regulation of leptin. [Diabetologia (1999) 42: 688±693]

Association of genetic variants of ghrelin, leptin and UCP2 with malnutrition inflammation syndrome and survival in end-stage renal disease patients

“…The ID gene polymorphism located in exon 8 of 3 0 UTR of UCP2 gene have been Fig. 2 a Hex generated GHreceptor-ghrelin complex for wild type, b Hex generated GHreceptor-ghrelin complex for mutant type previously reported to be associated with energy expenditure (Walder et al 1998), increased BMI (Cassell et al 1999), and accumulation of fat tissue (Pedersen et al 2005). In our study UCP2 ID showed protective effect.…”

Obesity and polymorphisms in genes regulating human adipose tissue

“…113,114 Additional UCP2 exon SNPs have been associated with basal metabolic rate or 24-h energy expenditure. [114][115][116] The phenotypic associations have not been confirmed in other populations. 117,118 UCP2 SNPs do not seem to regulate weight change.…”

The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

“…An association between the UCP2 exon 8 variant and body mass index was measured in two groups of South Indians [199]. This association was not observed in British subjects, but the UCP2 genotype of obese women was correlated with the serum leptin concentration, suggesting that the UCP2 variant may affect susceptibility to weight gain by influencing regulation of leptin [199]. No significant association between UCP2 polymorphisms and obesity or type II diabetes was noted by others [147,163,164,194,196,[198][199][200].…”

“…Walder et al [197] calculated that UCP2 gene polymorphisms were genetically associated with sleeping energy expenditure in Pima Indians, whereas no such association was found in a Scandinavian cohort [195]. An association between the UCP2 exon 8 variant and body mass index was measured in two groups of South Indians [199]. This association was not observed in British subjects, but the UCP2 genotype of obese women was correlated with the serum leptin concentration, suggesting that the UCP2 variant may affect susceptibility to weight gain by influencing regulation of leptin [199].…”