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

Am J Clin Nutr. 2014 Feb;99(2):392-9. doi: 10.3945/ajcn.113.072066. Epub 2013 Dec 11.


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 as NCT00072995.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Basal Metabolism
  • Blood Glucose / genetics
  • Blood Glucose / metabolism*
  • Circadian Rhythm / genetics*
  • Cryptochromes / genetics*
  • Cryptochromes / metabolism
  • Diet, Reducing*
  • Energy Metabolism*
  • Female
  • Genetic Loci
  • Genome-Wide Association Study
  • Genotype
  • Homeostasis / genetics
  • Humans
  • Linear Models
  • Male
  • Middle Aged
  • Obesity / diet therapy
  • Obesity / genetics
  • Overweight / diet therapy
  • Overweight / genetics
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Receptor, Melatonin, MT1 / genetics*
  • Receptor, Melatonin, MT1 / metabolism
  • Receptor, Melatonin, MT2


  • Blood Glucose
  • CRY2 protein, human
  • Cryptochromes
  • MTNR1B protein, human
  • Receptor, Melatonin, MT1
  • Receptor, Melatonin, MT2

Associated data