Research reportThe TaqIA RFLP is associated with attenuated intervention-induced body weight loss and increased carbohydrate intake in post-menopausal obese women☆
Highlights
► We examined the impact of the Taq1A polymorphism on weight loss by two modalities. ► Obese women performed 6 months of energy restriction by diet or by diet + exercise. ► A1+ (vs. A1−) carriers lost less body weight and fat mass in diet + exercise group. ► A1+ (vs. A1−) carriers increased carbohydrate intake in diet + exercise group. ► Novel findings are that Taq1A genotype differently impacts weight loss by modality.
Introduction
Of late there has been much focus on genotypes thought to be linked with impaired dopamine signaling. The surge in studies of dopamine and the role of its transport and receptor genes in feeding and other reward-driven behaviors such as ethanol consumption, gambling, drug-taking, and obesity strongly points to evidence of reward-related phenotypes (Noble, St. Jeor, et al., 1994). Support for the role of dopamine in human feeding behavior is evidenced in part by the anorexigenic action of dopamine agonists (Goldfield et al., 2007, Leddy et al., 2004, Schertz et al., 1996) and by the orexigenic action of dopamine antagonists (Roerig et al., 2005, Ruetsch et al., 2005). Dopamine is also involved in motor control and motivation (Salamone, Correa, Mingote, & Weber, 2005), and there is a body of evidence to suggest that dopaminergic activity in the brain is related to voluntary physical activity (for review see Knab and Lightfoot (2010)). Dopamine availability is dependent on its release, transport (reuptake), metabolism, and receptor binding. Consequently, by looking at the genes involved at any one of these functional stages there is an opportunity to indirectly investigate brain dopamine levels—in effect looking at markers of neurotransmitter activity (Epstein et al., 2007)—and how behavior may be resultantly impacted.
The TaqIA Restriction Fragment Length Polymorphism (RFPL) (rs1800497) is found within the ankyrin repeat and kinase domain containing-1 gene (ANKK1) (Neville, Johnstone, & Walton, 2004), located 10.5 kb downstream of the DRD2 gene in chromosome band 11q23.1 (Manning, Whyte, Martinez, Hunter, & Sudarsanam, 2002). This polymorphism is a single nucleotide C/T change; the T allele is referred to as A1, the C allele as A2, individuals hetero- or homozygous for the T allele are referred to as A1+, and individuals homozygous for the C allele are referred to as A1−. This polymorphism occurs in ANKK1 exon 8, and results in a glu713-to-lys (E713K) non-conservative substitution; to date, this substitution has not been associated with a change in ANKK1 structural integrity, substrate-binding specificity, or function, however, dopamine-related endophenotypes have been associated with the TaqI RFLP (Rodriguez-Jimenez et al., 2006). Moreover, ANKK1 and DRD2 genes have been shown to overlap, sharing halotypic blocks, and furthermore it was shown that ANKK1 expression was significantly upregulated by the powerful dopamine receptor agonist apomorphine (Hoenicka et al., 2010). Although the precise relationship between TaqIA RFLP and DRD2 remains uncertain, there is convincing evidence that A1+ individuals have a 30–40% reduction in D2 receptor density and availability in vivo (Jonsson et al., 1999, Noble et al., 1991, Pohjalainen et al., 1998, Thompson et al., 1997); it must be noted, however, that there are data showing no significant differences in dopamine binding potential between A1+ carriers and A1− (Laruelle, Gelernter, & Innis, 1998). Decreased striatal density of dopamine receptors has been shown via PET studies to be related to obesity (Volkow et al., 2008), even proportional to body mass (Wang et al., 2001). In line with the above noted hypo-responsiveness of dopamine transmission, evidence also suggests that the A1+ allele is related to body mass (Noble et al., 1994, Spitz et al., 1998, Thomas et al., 2001) but other groups have failed to find such a relationship (Davis et al., 2008, Jenkinson et al., 2000, Southon et al., 2003).
The TaqIA polymorphism has also been associated with a number of impulsive/addictive behaviors such as alcoholism (Munafo, Matheson, & Flint, 2007), smoking (Noble, 1998), and overeating leading to obesity (Noble et al., 1994, Spitz et al., 2000). Another phenotype associated with the TaqIA polymorphism is food preference. In a sample of obese men and women it was shown that 64.3% of those who preferred carbohydrates (as opposed to foods high in fat or protein) were carriers of the A1 allele, compared to the 21.1% of carriers who preferred either high fat or protein foods (Noble, Noble, et al., 1994). What is interesting are the recent findings, using fMRI to measure responsivity of brain reward circuitry to palatable food cues, suggesting that the A1+ allele is involved in consummatory and anticipatory feeding behavior. Specifically, individuals identified as having weaker striatal activation post-ingestion of a palatable food (Stice, Spoor, Bohon, Veldhuizen, & Small, 2008) or simply after imagining a palatable food (Stice, Yokum, Blum, & Bohon, 2010) had a greater risk of weight gain at 1 year, but only if they were an A1+ carrier (vs. A1−).
While obesity in general, and weight loss in particular, are no doubt influenced by polygenic factors, to our knowledge there has not been an effort to examine whether polymorphisms of TaqIA may impact the inter-individual variation in weight loss by two separate modalities. Accordingly, our primary objective was to investigate the potential association of the TaqIA RFLP allele with body weight loss in overweight/obese post-menopausal women who completed a 6-month weight loss intervention using caloric restriction (CR) with or without the addition of a resistance training (RT) program. Our secondary objective was to elucidate if there existed genotype associations with energy intake (EI) or energy expenditure variables (EE). It was hypothesized that individuals carrying the A1 allele would respond with reduced body weight loss to the caloric restriction intervention and that individuals carrying the A1 allele would display an enhanced carbohydrate (CHO) preference and attenuated physical activity energy expenditure (PAEE).
Section snippets
Methods
This is a secondary analysis of the Montreal Ottawa New Emerging Team weight loss intervention which was designed to reduce body weight (BW) by 10% and consisted of a 6-month intervention randomising participants to CR with or without resistance training (RT) (Brochu et al., 2009). The study was conducted according to the guidelines laid down in the Declaration of Helsinki, and all procedures involving human subjects/patients were approved by the Université de Montréal, Comité d’éthique de la
Results
At baseline, the average woman was 57.1 ± 4.6 years of age, BW of 86.5 ± 14.5 kg, BMI of 33.1 ± 4.4 kg/m2, FFM of 46.2 ± 6.8 kg, FM of 40.4 ± 9.3 kg, and % FM of 46.4 ± 4.5. There were no significant differences in initial BW or body composition at baseline neither by group nor by genotype.
TaqIA was in Hardy–Weinberg equilibrium and the frequencies of the TaqIA alleles were distributed as follows: six subjects (4.7%) were homozygous for the A1 allele, 60 subjects (47.2%) were heterozygous, and 61 (48.0%) were
Discussion
This study utilized a theoretically driven approach to elucidate possible relationships between the rs1800497 genotype believed to alter dopaminergic activity and the predisposition to respond differently to standardized weight loss modalities. Overall there was a significant association between the TaqIA genotype and BW loss, FM loss, and decrease in BMI post-intervention, but only for the women in the CRRT group. Regarding the secondary hypotheses, there was an association between the TaqIA
References (54)
- et al.
D2 dopamine receptor Taq1A polymorphism, body weight, and dietary intake in type 2 diabetes
Nutrition
(2009) - et al.
Genetic influences on the response of body fat and fat distribution to positive and negative energy balances in human identical twins
Journal of Nutrition
(1997) - et al.
The effects of prolonged caloric restriction leading to weight-loss on food hedonics and reinforcement
Physiology & Behavior
(2008) - et al.
Reward sensitivity and the D2 dopamine receptor gene. A case-control study of binge eating disorder
Progress in Neuro-Psychopharmacology and Biological Psychiatry
(2008) - et al.
Parent–child concordance of Taq1 A1 allele predicts similarity of parent–child weight loss in behavioral family-based treatment programs
Appetite
(2010) - et al.
Relation between food reinforcement and dopamine genotypes and its effect on food intake in smokers
American Journal of Clinical Nutrition
(2004) - et al.
Methylphenidate reduces energy intake and dietary fat intake in adults. A mechanism of reduced reinforcing value of food?
American Journal of Clinical Nutrition
(2007) - et al.
The ANKK1 gene associated with addictions is expressed in astroglial cells and upregulated by apomorphine
Biological Psychiatry
(2010) Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene. A review
European Psychiatry
(2000)- et al.
D2 dopamine receptor gene and cigarette smoking. A reward gene?
Medical Hypotheses
(1994)
Gene–exercise interactions
Progress in Molecular Biology and Translational Science
The TaqIA polymorphism linked to the DRD2 gene is related to lower attention and less inhibitory control in alcoholic patients
European Psychiatry
Psychotropic drugs induced weight gain. A review of the literature concerning epidemiological data, mechanisms and management
Encephale
Reinforcing value of food in obese and non-obese women
Appetite
Beyond the reward hypothesis. Alternative functions of nucleus accumbens dopamine
Current Opinion in Pharmacology
Variant alleles of the D2 dopamine receptor gene and obesity
Nutrition Research
Evaluation of a portable device to measure daily energy expenditure in free-living adults
American Journal of Clinical Nutrition
Anthropometric, metabolic, psychosocial, and dietary characteristics of overweight/obese postmenopausal women with a history of weight cycling. A MONET (Montreal Ottawa new emerging team) study
Journal of the American Dietetic Association
Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects. Possible contributing factors
Neuroimage
Brain dopamine and obesity
Lancet
Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors
Nature
Genetics of body-weight regulation
Nature
Increased prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with comorbid substance use disorder: a preliminary report
Pharmacogenetics
Resistance training does not contribute to improving the metabolic profile after a 6-month weight loss program in overweight and obese postmenopausal women
Journal of Clinical Endocrinology and Metabolism
Prevalence in the United States of selected candidate gene variants. Third national health and nutrition examination survey, 1991–1994
American Journal of Epidemiology
Correlation of the Taq1 dopamine D2 receptor gene and percent body fat in obese and screened control subjects: a preliminary report
Food & Function
Metabolic and behavioral characteristics of metabolically obese but normal-weight women
Journal of Clinical Endocrinology and Metabolism
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Acknowledgments: This study was supported by grants from the Canadian Institutes of Health Research (CIHR) New Emerging Team in Obesity (University of Montreal and University of Ottawa, MONET project-# OHN – 63279). Dr. Rabasa-Lhoret is supported the Fonds de la recherche en santé du Québec (FRSQ) and holds the Chair for clinical research J.-A. de Sève at IRCM (Montreal Institute for Clinical Research). Marie-Ève Riou is a recipient of the Frederick Banting and Charles Best Doctoral Award (CIHR). Conflict of Interest: None Disclosed