GAD2 on chromosome 10p12 is a candidate gene for human obesity.

The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.

Is restrained eating a risk factor for weight gain in a general population?

BACKGROUND: In modern societies characterized by abundant and accessible foods, restrained eating may become an adaptive behavior to limit weight gain. OBJECTIVE: We assessed the relations between eating behavior (EB) and adiposity in a general population over a 2-y period. DESIGN: We recruited 466 adults and 271 adolescents in 1999 on a geographical basis to participate in a longitudinal study. At the initial examination and 2 y later, they answered an EB questionnaire, the Three-Factor Eating Questionnaire-R18, which measured cognitive restraint (CR), uncontrolled eating, and emotional eating. On the same occasions, several measures of adiposity were also obtained: body mass index (BMI; in kg/m2), waist circumference, the sum of 4 skinfold thicknesses, and percentage body fat. Relations between EB and adiposity were tested separately in adults and adolescents by using mixed linear regressions after adjustment for age, sex, and (in adolescents) Tanner pubertal stage. RESULTS: At baseline, CR was positively associated with BMI in normal-weight subjects (mean BMI: 21.4 in the lowest to 23.3 in the highest CR quintile; P < 0.001) but not in overweight adults (P = 0.25). Initial CR did not predict change in adiposity variables (BMI change: P = 0.79 in adults, P = 0.57 in adolescents and young adults). Conversely, a high initial BMI was associated with a larger increase in CR (beta = 20.1, P < 0.0001 in adults; beta = 21.7, P = 0.003 in adolescents and young adults). CONCLUSIONS: Restrained eating is strongly associated with adiposity in normal-weight subjects but not in overweight subjects. However, restrained eating does not promote weight gain.

Polymorphisms in the amino acid transporter solute carrier family 6 (neurotransmitter transporter) member 14 gene contribute to polygenic obesity in French Caucasians.

Positional candidate gene analysis of the obesity-linked chromosome Xq24 locus identified two obesity-associated single nucleotide polymorphisms (SNPs) in the membrane amino acid transporter encoding the SLC6A14 (solute carrier family 6 [neurotransmitter transporter], member 14) gene in the Finnish population. Since we previously reported a modest evidence of linkage for this region in French obese families, we analyzed these SNPs in 1,267 obese adult case and 649 lean control subjects. SNPs 20649 C>T (odds ratio 1.23, 95% CI 1.04-1.45; P = 0.013) and 22510 C>G (1.36, 1.16-1.59; P = 0.0001) were shown to be associated with obesity in the French population. In addition, pedigree disequilibrium test results showed a modest excess of both at-risk SNP alleles in affected offspring (P = 0.05 and P = 0.08 for SNPs 20649 C>T and 22510 C>G, respectively). The SNP 22510 C>G at-risk G allele was associated, both in adult women with moderate obesity and in 234 obese girls, with higher body fat and modified perception of hunger and satiety (0.003 < P < 0.06). In conclusion, these data confirm an association of the SLC6A14 gene locus with obesity.

The Three-Factor Eating Questionnaire-R18 is able to distinguish among different eating patterns in a general population.

A revised version of the Three-Factor Eating Questionnaire (TFEQ) was developed in an obese population, but its applicability to the general population was not assessed. We aimed to define the relationship between eating behavior and reported food intake. This was a cross-sectional study of 529 middle-aged adults and 358 teenagers and young adults recruited on a geographical basis. The TFEQ-R18 measures 3 aspects of eating behavior: cognitive restraint (CR), uncontrolled eating (UE), and emotional eating. Reported food intake was calculated from a food frequency questionnaire. Girls who scored higher on restrained eating had a lower energy intake than the other girls (9164 kJ vs. 13,163 kJ, P < 0.001). In adult men, energy intake increased with UE (9663 kJ vs. 11,029 kJ in the lower and higher UE tertiles, respectively, P < 0.05). When specific food groups were analyzed, higher CR was positively associated in adults with healthy food groups like green vegetables [OR = 1.92 (0.68-2.44)] and negatively associated with French fries [OR = 0.35 (0.22-0.57)] and sugar [OR = 0.38 (0.23-0.61)]. Energy-dense foods, such as fat, were positively associated with UE [OR = 2.28 (1.46-3.57) for dietary fat]. Finally, emotional eaters had a higher snacking food intake. In teenagers and young adults, most associations were seen with CR. Converse to observations in adults, teenagers and young adults who exhibited a high cognitive restraint reported consumption of fewer energy-dense foods rather than more "healthy foods." The TFEQ-R18 was therefore able to distinguish among different eating patterns in our sample of a French general population.