Adrenergic Receptor β3
ADRB3 Trp64Arg T>C
The 1000 Genomes Project Database and the genome Aggregation Database (gnomAD) reports global frequencies of 11.5% and 9.06% respectively for C alelle (NIH).
A recent study comparing allele frequencies of various β-adrenergic receptors (ARs) in a Southeastern European Caucasian population versus other populations reported a global frequency of 11.50% for the variant allele (Arg64). The frequency has however been reported as much higher in Alaskan Eskimos and Pima Indians with frequencies of 38% and 31% respectively for Arg64.
ADBR3 Gene Detail
The β-3 AR, primarily expressed in adipose tissue, is thought to act as an important trigger of lipolysis in white adipose tissue in response to fasting, as well as of thermogenesis within brown adipose tissue in response to cold exposure or overfeeding. This implies its essential role in energy balance and metabolism.
The Trp64Arg polymorphism has been associated with various obesity-related traits such as body mass index (BMI) and larger waist to hip ratio in several, although not all, ethnic groups. It has also been shown that individuals with the Arg64-allele (TC and CC genotypes) may experience weight loss resistance, while the Trp64-allele seems protective against obesity. Research do however present some contradictory findings regarding this association and it has been suggested that the polymorphism may display ethnic heterogeneity.
ADBR3 Trp64Arg T>C
The β-ARs are considered essential components of the sympathetic nervous system. These receptors belong to the G protein-coupled receptors superfamily and their signalling pathway is stimulated by the endogenous catecholamines, epinephrine and norepinephrine. The β-3 AR promotes lipolysis and fat mobilisation, whilst it is also suggested to modify glucose metabolism.
Ten SNPs have been identified within the coding region of the ADBR3 gene. The amino acid change from tryptophan to arginine at codon 64 is said to result in structural and functional changes as the receptor’s ability to maximally activate cAMP formation is affected. This missense mutation is reported to disrupt receptor binding, signal transduction and regulatory mechanisms which may all lead to a lower resting metabolic rate and diminished lipolysis in visceral adipose tissue.
Clement et al. (1995) first proposed that this mutation may be responsible for weight changes in obese individuals in 1995; interestingly, this mutation is however not found to influence the pharmacological properties of the β-3 AR. Population studies have associated the Arg64 variant with a decreased metabolic rate, higher BMI and greater risk for abdominal obesity together with increased risk for developing essential hypertension, although the last-mentioned results seem inconsistent.
A large meta-analysis reported that the Arg64 variant contributes to susceptibility to weight gain in East Asians, although this is not confirmed in Caucasian participants. The Arg64 variant has also been associated with increased visceral adiposity and insulin resistance in humans, possibly due to the mutated β-3 AR displaying reduced lipolytic activity and retention of lipids in white adipocytes.
Contradicting findings were reported by Zaharan et al. (2018) when their cross-sectional study with 1151 15-year old Malaysian adolescents revealed that the CC genotype was associated with a small but protective effect on adiposity. This study, as part of the Malaysian Health and Adolescents Longitudinal Research Team study (MyHeARTs), reported that those participants homozygous for the Arg64 allele had reduced body fat percentages.
A study from Yamakita et al. (2010) followed 145 obese Japanese men for four years to determine whether the Trp64Arg polymorphism was associated with long term weight changes. Individuals carrying the Arg64-allele (CT and CC genotypes) were found to gain weight more readily than those without the Arg64-allele (TT genotype), although no significant difference in weight or BMI was found at baseline. After 4 years, Arg64 carriers showed significant increases in body weight and BMI, whereas non-carriers (TT genotypes) demonstrated a slight, although not significant, weight loss and decrease in BMI. Research suggests that that the presence of the Arg64-allele seems to discourage weight loss. Takeuchi et al. (2012) also found that, in young and generally healthy Japanese men, the Arg/Arg genotype was associated with annual BMI gain.
A more recent randomized controlled trial from Sakane et al. (2016) investigated whether the Trp64Arg polymorphism could modulate the effects of lifestyle intervention on weight and metabolic parameters in patients with impaired glucose tolerance, as part of the Japan Diabetes Prevention Program. Non-carriers (TT genotypes) in both the intervention and control groups demonstrated a significantly greater weight and BMI reduction compared to Arg64 carriers.
In support of the findings from Yamakita et al. (2010) as well as Szendrei et al. (2016), baseline measures revealed no significant differences in body weight, BMI and / or waist circumference. Also, Takeuchi et al. (2012) did not find the Trp64Arg polymorphism associated with current BMI in young and generally healthy Japanese men at baseline.
A very recent study from Daghestani et al. (2018) found the Arg64-allele frequency to be significantly higher in overweight and obese subjects of a Saudi population compared to the normal weight subjects. The authors concluded that in their study, the Arg64-allele significantly associated with a greater body weight and elevated BMI in the Saudi population.
Although the long-term effect of the Trp64Arg polymorphism on obesity-related traits is somewhat controversial, this effect also seems to be modified by the weight status of participants. Several long-term longitudinal studies in Japanese subjects reported no association between the Trp64Arg polymorphism in non-obese participants, while some studies have reported this associated weight gain particularly in obese subjects.
Several studies have reported an association between the Trp64Arg polymorphism and weight loss in response to a diet and exercise intervention, particularly in obese American and Japanese women. Obese diabetic and non-diabetic subjects with the Trp64Arg polymorphism were also found to be resistant to a low-calorie diet and exercise. The resultant decline in resting metabolic rate and visceral lipolysis in Arg64 carriers may explain the poor response to lifestyle intervention.
In a study part of the randomized controlled trial Nutrition and Physical Activity Programs for Obesity Treatments (PRONAF study according to its Spanish initials) which involved a 6-month diet and exercise-based program, Szendrei et al. (2016) reported that carriers of the Arg64-allele had lost less fat mass and reduced percentage fat than did non-carriers. All participants were placed on a hypocaloric diet with 25-30% calorie restriction from their habitual intake and were randomly placed into an exercise group. It was also previously reported that after a 13-month long diet program, Arg64 carriers lost 43% less visceral adipose tissue than Trp64-homozygotes.
In contrast, a single intervention study from Saliba et al. (2014) found that the Trp64Arg polymorphism did not moderate weight loss in obese Brazilian women after a 7-week dietary intervention.
The Trp64Arg polymorphism has been shown to control fat oxidation during exercise. According to a study from Morita et al. (2009) healthy young Japanese men carrying the Arg64 allele produced less fat oxidation during exercise.
A previous study has shown that in response to endurance exercise training, subjects with the Arg64-alelle displayed a 2-fold greater loss in fat mass compared to non-carriers. This suggests that although the polymorphism may induce weight loss resistance, with adequate levels of physical activity, Arg64-carriers may still be able to lose weight.
In the randomized control trial from Szendrei et al. (2016) it was reported that among the Arg64 carriers, the control group that were non-supervised with exercise had higher fat mass values than the intervention group which received supervised strength, endurance or combined training; this may suggest that supervised exercise is beneficial for these genotypes. The relevant authors have suggested there may be a higher obesity risk in sedentary carriers as compared to active people carrying the variant (Arg64) allele. This is in line with an earlier study from Marti et al. (2002) where the Trp64Arg polymorphism was suggested to be a risk factor for obesity among inactive but not in physically active individuals.
This agrees with findings from Bea et al. (2010) where following a 12-month resistance training program, sedentary post-menopausal women who carries the Arg64-allele gained a greater percentage of fat than did non-carriers.
Beta 1, Beta 2 and Beta 3 Adrenergic
Receptor Gene Polymorphisms in a
Southeastern European Population
Katsarou et al, 2018.