Satiety mechanisms in genetic risk of obesity

Abstract

Importance: A better understanding of the cause of obesity is a clinical priority. Obesity is highly heritable, and specific genes are being identified. Discovering the mechanisms through which obesity-related genes influence weight would help pinpoint novel targets for intervention. One potential mechanism is satiety responsiveness. Lack of satiety characterizes many monogenic obesity disorders, and lower satiety responsiveness is linked with weight gain in population samples.

Objective: To test the hypothesis that satiety responsiveness is an intermediate behavioral phenotype associated with genetic predisposition to obesity in children.

Design, setting, and participants: Cross-sectional observational study of a population-based cohort of twins born January 1, 1994, to December 31, 1996 (Twins Early Development Study). Participants included 2258 unrelated children (53.3% female; mean [SD] age, 9.9 [0.8] years), one randomly selected from each twin pair.

Exposure: Genetic predisposition to obesity. We created a polygenic risk score (PRS) comprising 28 common obesity-related single-nucleotide polymorphisms identified in a meta-analysis of obesity-related genome-wide association studies.

Main outcomes and measures: Satiety responsiveness was indexed with a standard psychometric scale (Child Eating Behavior Questionnaire). Using 1990 United Kingdom reference data, body mass index SD scores and waist SD scores were calculated from parent-reported anthropometric data for each child. Information on satiety responsiveness, anthropometrics, and genotype was available for 2258 children. We examined associations among the PRS, adiposity, and satiety responsiveness.

Results: The PRS was negatively related to satiety responsiveness (β coefficient, -0.060; 95% CI, -0.019 to -0.101) and positively related to adiposity (β coefficient, 0.177; 95% CI, 0.136-0.218 for body mass index SD scores and β coefficient, 0.167; 95% CI, 0.126-0.208 for waist SD scores). More children in the top 25% of the PRS were overweight than in the lowest 25% (18.5% vs 7.2%; odds ratio, 2.90; 95% CI, 1.98-4.25). Associations between the PRS and adiposity were significantly mediated by satiety responsiveness (P = .006 for body mass index SD scores and P = .005 for waist SD scores).

Conclusions and relevance: These results support the hypothesis that low satiety responsiveness is one of the mechanisms through which genetic predisposition leads to weight gain in an environment rich with food. Strategies to enhance satiety responsiveness could help prevent weight gain in genetically at-risk children.

Figure 1

Regression of mean age- and sex-adjusted BMI-SDS and waist-SDS values across the risk-allele scores. The histogram shows that the number of weighted obesity risk alleles was normally distributed in the sample. The black triangles show the mean age- and sex-adjusted BMI-SDS values across the weighted risk-allele scores; the blue diamonds show the mean age- and sex-adjusted waist-SDS values across the weighted risk-allele scores. The solid black line shows the regression line for age- and sex-adjusted BMI-SDS predicted from the polygenic obesity risk score (R², 0.031; beta, 0.177; beta 95% CI, 0.136 to 0.218). The solid blue line shows the regression line for age- and sex-adjusted waist-SDS predicted from the polygenic risk score (R², 0.028; beta, 0.167; beta 95% CI, 0.126 to 0.208).

Figure 2

Regression of the mean age- and sex-adjusted Satiety Responsiveness values across the risk-allele scores. The histogram shows that the number of weighted obesity risk alleles was normally distributed in the sample. The purple circles show the mean age- and sex-adjusted Satiety Responsiveness scores across the weighted risk-allele scores. The solid purple line shows the regression line for age- and sex-adjusted Satiety Responsiveness predicted from the polygenic obesity risk score (R², 0.004; beta, −0.060; beta 95% CI, −0.101 to −0.019).

Figure 3

Path diagram showing that Satiety Responsiveness significantly mediates the association between polygenic risk of obesity and BMI-SDS. The path diagram shows the simple association between the polygenic risk score (PRS) and Satiety Responsiveness (beta, −0.060; 95% CI, −0.101 to −0.019), the association between the PRS and BMI-SDS adjusted for Satiety Responsiveness (beta, 0.164; 95% CI, 0.125 to 0.203), and the association between Satiety Responsiveness and BMI-SDS adjusted for the PRS (beta, −0.219; 95% CI, −0.258 to −0.180). The simple association between the PRS and BMI-SDS (beta, 0.177; 95% CI, 0.136 to 0.218) was slightly higher than the association between the PRS and BMI-SDS adjusted for Satiety Responsiveness (beta Δ 0.013), indicating that Satiety Responsiveness mediated part of the association. The Sobel test confirmed that Satiety Responsiveness significantly mediated the association between the PRS and BMI-SDS (P=0.006).

Figure 4

Path diagram showing that Satiety Responsiveness significantly mediates the association between polygenic risk of obesity and waist-SDS. The path diagram shows the simple association between the polygenic obesity risk score (PRS) and Satiety Responsiveness (beta, −0.060; 95% CI, −0.101 to −0.019), the association between the PRS and waist-SDS adjusted for Satiety Responsiveness (beta, 0.153; 95% CI, 0.114 to 0.192), and the association between Satiety Responsiveness and waist-SDS adjusted for the PRS (beta, −0.235; 95% CI, −0.274 to −0.196). The simple association between the PRS and waist-SDS (beta, 0.167; 95% CI, 0.126 to 0.208) was slightly higher than the association between the PRS and waist-SDS adjusted for Satiety Responsiveness (beta Δ 0.016), indicating that Satiety Responsiveness mediated part of the association. The Sobel test confirmed that Satiety Responsiveness significantly mediated the association between the PRS and waist-SDS (P=0.005).