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Original Investigation |

Satiety Mechanisms in Genetic Risk of Obesity

Clare H. Llewellyn, PhD1,2; Maciej Trzaskowski, PhD, MSc2; Cornelia H. M. van Jaarsveld, PhD1; Robert Plomin, PhD2; Jane Wardle, PhD1
[+] Author Affiliations
1Health Behaviour Research Centre, Department of Epidemiology and Public Health, University College London, London, England
2Division of Health and Social Care Research, King’s College London, London, England
JAMA Pediatr. 2014;168(4):338-344. doi:10.1001/jamapediatrics.2013.4944.
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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.

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Figures

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Figure 1.
Regression of the Mean Age-Adjusted and Sex-Adjusted Body Mass Index SD Score (BMI-SDS) and Waist Circumference SD Score (Waist-SDS) Across the Risk Allele Scores

The number of weighted obesity risk alleles was normally distributed in the sample. The triangles show the mean age-adjusted and sex-adjusted BMI-SDS across the weighted risk allele scores. The circles show the mean age-adjusted and sex-adjusted waist-SDS across the weighted risk allele scores. The solid line shows the regression line for age-adjusted and sex-adjusted BMI-SDS predicted from the polygenic risk score (R2 = 0.031; β coefficient, 0.177; 95% CI, 0.136-0.218). The dashed line shows the regression line for age-adjusted and sex-adjusted waist-SDS predicted from the polygenic risk score (R2 = 0.028; β coefficient, 0.167; 95% CI, 0.126-0.208).

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Figure 2.
Regression of the Mean Age-Adjusted and Sex-Adjusted Satiety Responsiveness Across the Risk Allele Scores

The number of weighted obesity risk alleles was normally distributed in the sample. The circles show the mean age-adjusted and sex-adjusted satiety responsiveness across the weighted risk allele scores. The solid line shows the regression line for age-adjusted and sex-adjusted satiety responsiveness predicted from the polygenic risk score (R2 = 0.004; β coefficient, −0.060; 95% CI, −0.101 to −0.019).

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Figure 3.
Path Diagram Showing That Satiety Responsiveness Significantly Mediates the Association Between Polygenic Risk of Obesity and Body Mass Index SD Score (BMI-SDS)

The path diagram shows the simple association between the polygenic risk score (PRS) and satiety responsiveness, the association between the PRS and BMI-SDS adjusted for satiety responsiveness, and the association between satiety responsiveness and BMI-SDS adjusted for the PRS. The simple association between the PRS and BMI-SDS (β coefficient, 0.177; 95% CI, 0.136-0.218) was slightly higher than the association between the PRS and BMI-SDS adjusted for satiety responsiveness (change in β coefficient, 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 = .006).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Path Diagram Showing That Satiety Responsiveness Significantly Mediates the Association Between Polygenic Risk of Obesity and Waist Circumference SD Score (Waist-SDS)

The path diagram shows the simple association between the polygenic risk score (PRS) and satiety responsiveness, the association between the PRS and waist-SDS adjusted for satiety responsiveness, and the association between satiety responsiveness and waist-SDS adjusted for the PRS. The simple association between the PRS and waist-SDS (β coefficient, 0.167; 95% CI, 0.126-0.208) was slightly higher than the association between the PRS and waist-SDS adjusted for satiety responsiveness (change in β coefficient, 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 = .005).

Graphic Jump Location

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