Uncoupling Protein 1, 2, and 3
UCP1 -3826 A>G, UCP2 -866 G>A, UCP3 -55 C>T
UCP1 -3826 A>G
The 1000 Genomes Project Database and the genome Aggregation Database (gnomAD) reports global frequencies of 46.8% and 38.9% respectively (NIH) in G alleles. In a Malaysian population: 61% in Malay, 55% in Chinese, 52% in Indian.
UCP2 -866 G>A
The 1000 Genomes project and the genome Aggregation Database (gnomAD) reports global frequencies of 59.1% and 59.77% respectively (NIH) in G alleles.
UCP3 -55 C>T
The 1000 Genomes project and the genome Aggregation Database (gnomAD) reports global frequencies of 81.4% and 76.44% respectively (NIH) in C alleles.
The mitochondrial uncoupling proteins (UCPs) 1, 2 and 3 are described as members of an anion-carrier protein family located in the inner mitochondrial membrane. Although these three proteins are structurally similar, they are expressed in different tissues and present with tissue-specific functions.
UCPs are said to decrease metabolic efficiency and reduce adenosine triphosphate (ATP) production by uncoupling the mitochondrial synthesis of ATP from substrate oxidation through the respiratory chain. This uncoupling is achieved by promoting the net translocation of protons from the intermembrane space, across the inner mitochondrial membrane towards the mitochondrial matrix. UCPs thus transfer food energy directly into heat instead of ATP.
The UCP genes are considered candidate genes for obesity and other metabolic concerns because mutations may result in reduced protein activity and resultant deregulation of energy expenditure, thermogenesis and the reduction of oxidative stress. There is evidence that polymorphisms in the UCPs may be associated with obesity risk, BMI changes, prediabetes, type 2 diabetes mellitus (T2DM) and insulin resistance, although findings are somewhat controversial and seem influenced by ethnicity. It is suggested that these ethnic differences could potentially be ascribed to different lifestyles, environments and body weight distributions, different genotype frequencies as well as different dietary patterns.
UCP1: The G-allele is associated with reduced resting energy expenditure and thermogenesis.
UCP2: The A-allele is associated with protection against obesity.
UCP3: Some conflicting results; however the research weight shows that the T allele appears to be protective against obesity.
UCP1 -3826 A>G; UCP2 -866 G>A; UCP3 -55 C>T
UCP1 -3826 A>G
UCP1 is predominantly expressed in brown adipose tissue (BAT) where it is involved in thermogenesis and energy expenditure. Evidence suggests that, in adult humans, the activation of BAT occurs under cold-stress conditions and that the activity of BAT is reduced with age – inactive BAT is thought to be linked to reduced energy expenditure and age-induced obesity. UCP1 is also said to play a role in reducing the formation of reactive oxygen species (ROS) together with UCP2 and UCP3.
The UCP1 -3826 A>G polymorphism was first identified in 1994, when a pilot study associated it with obesity and weight gain. The SNP is located within a transcriptional enhancer site of UCP1 and the G-allele has been shown to reduce the transcriptional activity of UCP1. The expression of UCP1 in BAT is reportedly activated by sympathetic nervous system (SNS) activity, with the G-allele linking to reduced BAT activity.
A recent case-control study from Chathoth et al. utilised obese and non-obese healthy control subjects of Saudi-origin, to find a significant association between the UCP1 SNP and obesity, BMI and other obesity-related parameters. In addition, the authors observed a significantly increased risk allele frequency (G-allele) with lower HDL and higher LDL and triglycerides in the moderate-obese (BMI ≥ 30–39.9 kg/m2) cohort than in the extreme-obese (BMI ≥ 40 kg/m2) and control (BMI < 30 kg/m2) cohorts. There was also a significant number of diabetic patients in both moderate-obese (four-fold increase) and extreme-obese cohorts (two-fold increase) compared to the control cohort.
In contrast, the meta-analysis from Brondani et al. found no significant association between the UCP1 SNP and mean BMI differences in European or Asian populations. Although a study amongst healthy, young female adult Japanese subjects also found no association between the UCP1 SNP and anthropometric measures, it did report a significantly lower resting energy expenditure (REE) in G-allele carriers as well as reduced thermoregulatory SNS activity in GG homozygotes. Nagai et al. suggested that both these effects observed in their study may be due to attenuated UCP1-linked thermogenesis, indicating that BAT does contribute to the regulation of whole-body energy expenditure.
Interestingly, this attenuated thermogenic effect may be seasonally dependent. A study from Nakayama et al. reported that the G-allele significantly associated with an increased visceral fat area in Japanese adults when sampled in the cold season, whereas those sampled in the hot season showed no association. This implies that G-allele carriers may be at an increased risk for visceral fat accumulation during winter months (strongly correlated with outside temperature but not night length), more than during summer months, due to reduced BAT-activated thermogenesis and lowered REE.
The study from Nagai et al. also found that GG homozygotes consumed a significantly lower proportion of energy as fat, but a significantly greater proportion of energy as carbohydrates. In a similar study, GG homozygosity influenced post-prandial thermogenesis after a high-fat meal (70% fat of energy), suggesting that this allele may attenuate fat utilization in BAT metabolism – presumably, the G-allele influences appetite and/or food preference because of this altered lipid utilisation in BAT.
Associations for this SNP, however, seem highly controversial in different ethnic study populations.
UCP2 -866 G>A
UCP2 is distributed across a wide range of tissue types such as white adipose tissue, skeletal muscle and pancreatic islets; it is reportedly involved in the regulation of free fatty acid (FFA) metabolism, ATP-dependent processes, macrophage-mediated immunity as well as in the reduction of the formation of ROS together with UCP1 and UCP3. It is suggested that UCP2 has a role in beta-cell glucose sensing, in the regulation of insulin secretion and in counteracting diet-induced obesity by enhancing peripheral fatty acid metabolism – some reports found that UCP2 expression appeared to be up-regulated in response to a high fat diet.
UCP2 and UCP3 genes are adjacently situated on chromosome 11q13 and these gene clusters are said to potentially play important roles in energy metabolism and body mass regulation.
The UCP2 -866 G>A polymorphism, present in the promoter region of the UCP2 gene, seems to be involved in the supposed binding sites for specific transcription factors with many studies suggesting this to cause altered gene activity. Although research findings are conflicted in whether this SNP results in increased or reduced UCP2-mRNA levels, differentiated adipocytes expressing the A-allele have demonstrated a 22% increase in transcriptional activity. Brondani et al. have speculated that this would make sense as increased UCP2 activity would result in increased energy expenditure and a reduced BMI, while Qian et al. suggested that the opposing rates of mRNA expression could potentially contribute to the understanding of differences seen across ethnic groups. The rs659366 SNP has been linked to higher UCP2 mRNA levels, reduced insulin secretion and sensitivity as well as increased T2DM risk.
Considering 56 studies in a meta-analysis, Brondani et al. reported a significant interaction between the A-allele and a reduced BMI in Europeans. This finding is supported by a meta-analysis that included 42 studies from Zhang et al., in which the authors suggested a protective effect of the A-allele against obesity in Europeans. Andersen et al., although utilising a much smaller meta-analysis of 8 studies, also reported that European A-allele carriers may experience a protective effect against obesity.
A longitudinal study from Salopuro et al. evaluating whether UCP2 and UCP3 SNPs were associated with obesity and diabetes-related traits in subjects participating in the Finnish Diabetes Prevention Study, reported no association between the UCP 2 SNP and weight, BMI nor T2DM risk. The authors did however find that A-allele carriers had lower waist circumferences and WHR at baseline, but also lower insulin secretion at the 3-year follow-up.
In a Balinese population however, Oktavianthi et al. found that urban subjects with AA genotype had a higher BMI than rural subjects with the same genotype, suggesting that environment may play an influential role. In a study that involved Korean women undergoing a very low-calorie program, the AA homozygotes lost less weight than carriers of the G-allele, suggesting a slight weight loss resistance in some ethnicities. Although the authors observed no significant association with other obesity-related traits, previous studies have reported associations of the A-allele with increased HDL levels and decreased LDL levels in a Chinese population; another study also reported that individuals homozygous for the A-allele presented with significantly reduced LDL-particle size which is linked to an increased risk for coronary heart disease.
Brondani et al. found that Danish G-allele carriers steadily presented with lower insulin sensitivity while some evidence has shown that over-expression of UCP2 was associated with reduced insulin secretion. Two meta-analyses, from Xu et al. and De Souza et al., considering 17 and 23 studies respectively, however, found no significant association with T2DM risk in either Asian or European populations. A case-control study, also from De Souza et al. and involving a population of European descent, similarly found no significant association with T2DM risk.
UCP3 -55 C>T
UCP3 is mainly expressed in skeletal muscle where it is also involved in the regulation of FFA metabolism, ATP-dependent substrate oxidation and in the reduction of the formation of ROS together with UCP1 and UCP2. It is suggested to play a role in protecting the mitochondria against lipotoxicity.
The UCP3 -55 C>T SNP is thought to be a functional polymorphism, located upstream of the most commonly used transcription initiation site of skeletal muscle. The location of this SNP, close to the TATA box and downstream of a supposed peroxisome proliferator-activated receptor (PPAR) responsive element, indicates that it could alter PPAR-γ responsiveness of the UCP3 gene in modulating lipid metabolism and insulin sensitivity. Lower UCP3 mRNA and protein levels are reportedly present in T2DM patients.
In Pima Indians, the T-allele increased UCP3 mRNA expression in skeletal muscle compared with the C-allele, and the expression level correlated negatively with BMI. Liu et al. also reported that T-allele carriers had an average of 3.5% lower BMI.
Lee et al. found that among Malaysian participants of Chinese descent, T-allele carriers had a significant 30% risk reduction in central adiposity – measured as WHR. The authors suggested that there may be a synergy in the effect on obesity and obesity-related traits as the SNP alone did not associate with BMI, but a combinatory genotype and allele analysis revealed that participants with UCP1 AA and UCP3 CC genotypes had highest BMI and body fat percentages. Similarly, Korean children carrying the CC genotype had significantly higher waist circumferences compared to other genotypes.
In contrast to this, a significant association was reported between the rs1800849 SNP and BMI, whereby Asian TT homozygotes presented with a higher BMI. In Germans and South Indian females, T-allele carriers presented with increased waist-to-hip ratio (WHR). Salopuro et al. found a significant association between the T-allele and elevated total cholesterol and LDL concentrations at the baseline of their longitudinal study; they also reported on a study that associated the T-allele with lower HDL levels.
The longitudinal study from Salopuro et al. evaluating whether UCP2 and UCP3 SNPs were associated with obesity and diabetes-related traits in subjects participating in the Finnish Diabetes Prevention Study, reported no association between the UCP 3 SNP with weight, BMI nor T2DM risk. A meta-analysis from Qian et al. found no association with obesity in Asian or European subjects, neither did studies in Pima Indians, Japanese and Danish populations.
After a 3-month high-monounsaturated fat hypocaloric dietary intervention in obese participants, the prospective study from De Luis et al. reported that CC homozygotes had a greater decrease in BMI, weight, fat mass and waist circumference than T-allele carriers. In addition, CC homozygotes presented with significant reductions in total cholesterol and LDL levels, whereas T-allele carriers had no change in biochemical parameters in response to the dietary intervention. The authors mentioned that in their previous study involving two different dietary interventions (low carbohydrate versus low fat hypocaloric diets), although both genotypes resulted in significant anthropometric parameter reductions, the T-allele again did not present with any significant change in biochemical parameters.
Two meta-analyses, from Xu et al. and De Souza et al. have reported significant associations with T2DM risk in Asians, but not Europeans. A case-control study from De Souza et al., involving a population of European descent, similarly found no significant association with T2DM risk in this ethnicity group. A case-control study in a rural adult Chinese population of type 2 diabetics, prediabetics and those with normal glucose tolerance (NGT), reported a significant association with prediabetes, but not with T2DM.
Liu et al. The Role of Uncoupling Proteins in Diabetes Mellitus. Journal of Diabetes Research. 2013.
UCP1: G Allele
Since the G-allele is reportedly associated with lower REE and decreased ability to burn fat, it is recommended that weight loss goals remain realistic with regular follow-up appointments and is complimented with activities increasing energy expenditure.
UCP2: A Allele
The A-allele is reportedly associated with increased expression, thus also a reduced risk for obesity in Caucasian individuals. Research suggests that the G-allele may benefit from energy restriction as a hypocaloric diet increased the expression of UCP2.
UCP3: C Allele
Research findings are somewhat controversial – the T-allele has been reported to reduce the risk for obesity with energy restriction potentially increasing the expression of UCP3 and assisting weight loss in C-allele carriers.
Association of Uncoupling Protein 1 (UCP1) gene polymorphism with obesity: a case-control study
Chathoth et al, 2018.