Variants in glucose- and circadian rhythm-related genes affect the response of energy expenditure to weight-loss diets: the POUNDS LOST Trial

Abstract

Background: Circadian rhythm has been shown to be related to glucose metabolism and risk of diabetes, probably through effects on energy balance. Recent genome-wide association studies identified variants in circadian rhythm-related genes (CRY2 and MTNR1B) associated with glucose homeostasis.

Objective: We tested whether CRY2 and MTNR1B genotypes affected changes in measures of energy expenditure in response to a weight-loss diet intervention in a 2-y randomized clinical trial, the POUNDS (Preventing Overweight Using Novel Dietary Strategies) LOST Trial.

Design: The variants CRY2 rs11605924 (n = 721) and MTNR1B rs10830963 (n = 722) were genotyped in overweight or obese adults who were randomly assigned to 1 of 4 weight-loss diets that differed in their proportions of macronutrients. Respiratory quotient (RQ) and resting metabolic rate (RMR) were measured.

Results: By 2 y of diet intervention, the A allele of CRY2 rs11605924 was significantly associated with a greater reduction in RQ (P = 0.03) and a greater increase in RMR and RMR/kg (both P = 0.04). The G allele of MTNR1B rs10830963 was significantly associated with a greater increase in RQ (P = 0.01) but was not related to changes in RMR and RMR/kg. In addition, we found significant gene-diet fat interactions for both CRY2 (P-interaction = 0.02) and MTNR1B (P-interaction < 0.001) in relation to 2-y changes in RQ.

Conclusions: Our data indicate that variants in the circadian-related genes CRY2 and MTNR1B may affect long-term changes in energy expenditure, and dietary fat intake may modify the genetic effects. This trial was registered at www.clinicaltrials.gov as NCT00072995.

Figures

FIGURE 1.

Interaction between the CRY2 or MTNR1B genotype and dietary fat intervention on change in RQ at 2 y. P-interactions between single nucleotide polymorphism and the low-fat or high-fat diet after adjustment for age, sex, ethnicity, and baseline weight are presented. Data included 57 and 58 (AA), 122 and 117 (AC), and 53 and 49 (CC) participants in the low-fat group and the high-fat group, respectively, at 2 y (total n = 456) in the CRY2 gene and 123 and 120 (CC), 86 and 82 (CG), and 24 and 20 (GG) participants in the low-fat group and the high-fat group, respectively, at 2 y (total n = 455) in the MTNR1B gene. A post hoc analysis that used Tukey's procedure showed significant differences in RQ change between the CC and GG genotypes in the low-fat diet group (P = 0.004). RQ, respiratory quotient.

FIGURE 2.

Interaction between the CRY2 rs11605924 genotype and the dietary fat intervention on RQ changes during a 2-y intervention. P-interactions between single nucleotide polymorphism and the low-fat or high-fat diet after adjustment for age, sex, ethnicity, and baseline weight are presented. Data included 110 and 101 (AA), 170 and 171 (AC), and 83 and 85 (CC) participants in the low-fat group and the high-fat group, respectively, at baseline (total n = 720); 80 and 72 (AA), 145 and 147 (AC), and 70 and 68 (CC) participants in the low-fat group and the high-fat group, respectively, at 6 mo (total n = 582); and 57 and 58 (AA), 122 and 117 (AC), and 53 and 49 (CC) participants in the low-fat group and the high-fat group, respectively, at 2 y (total n = 456). A post hoc analysis showed no significant difference between pairwise analyses of the genotypes. RQ, respiratory quotient; VCO2, carbon dioxide consumption; VO2, oxygen consumption.

FIGURE 3.

Interaction between MTNR1B rs10830963 genotype and the dietary fat intervention on RQ changes during the 2-y intervention. P-interactions between single nucleotide polymorphism and the low-fat or high-fat diet after adjustment for age, sex, ethnicity and baseline weight are presented. Data included 198 and 194 (CC), 134 and 139 (CG), and 31 and 25 (GG) participants in the low-fat group and the high-fat group, respectively, at baseline (total n = 721); 156 and 152 (CC), 113 and 111 (CG), and 27 and 23 (GG) participants in the low-fat group and the high-fat group, respectively, at 6 mo (total n = 582); and 123 and 120 (CC), 86 and 82 (CG), and 24 and 20 (GG) participants in the low-fat group and the high-fat group, respectively, at 2 y (total n = 455). A post hoc analysis that used Tukey's procedure showed significant differences in the 2-y RQ change between CC and GG genotypes in the low-fat diet group (P = 0.004) and in the 6-mo RQ change between the CC and CG (P = 0.008) and CG and GG (P = 0.03) genotypes in the high-fat diet group. RQ, respiratory quotient; VCO2, carbon dioxide consumption; VO2, oxygen consumption.