Genetic determinant for amino acid metabolites and changes in body weight and insulin resistance in response to weight-loss diets: the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial

Circulation. 2013 Mar 26;127(12):1283-9. doi: 10.1161/CIRCULATIONAHA.112.000586. Epub 2013 Feb 27.


Background: Circulating branched-chain amino acids and aromatic amino acids were recently related to insulin resistance and diabetes mellitus in prospective cohorts. We tested the effects of a genetic determinant of branched-chain amino acid/aromatic amino acid ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial.

Methods and results: We genotyped the branched-chain amino acid/aromatic amino acid ratio-associated variant rs1440581 near the PPM1K gene in 734 overweight or obese adults who were assigned to 1 of 4 diets varying in macronutrient content. At 6 months, dietary fat significantly modified genetic effects on changes in weight, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) after adjustment for the confounders (all P for interaction ≤0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all P ≤ 0.02 in an additive pattern), whereas an opposite genotype effect on changes in insulin and HOMA-IR was observed in the low-fat diet group (P=0.02 and P=0.04, respectively). At 2 years, the gene-diet interactions remained significant for weight loss (P=0.008) but became null for changes in serum insulin and HOMA-IR resulting from weight regain.

Conclusions: Individuals carrying the C allele of the branched-chain amino acid/aromatic amino acid ratio-associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertaking an energy-restricted high-fat diet.

Clinical trial registration: URL: Unique identifier: NCT00072995.

Publication types

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

MeSH terms

  • Adult
  • Alleles
  • Amino Acids, Aromatic / metabolism*
  • Amino Acids, Branched-Chain / metabolism*
  • Body Weight / genetics*
  • Diet, Reducing*
  • Female
  • Genetic Determinism*
  • Genotype
  • Homeostasis
  • Humans
  • Insulin / blood
  • Insulin Resistance / genetics*
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Obesity / diet therapy*
  • Obesity / prevention & control
  • Phosphoprotein Phosphatases / genetics
  • Protein Phosphatase 2C
  • Treatment Outcome


  • Amino Acids, Aromatic
  • Amino Acids, Branched-Chain
  • Insulin
  • PPM1K protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C

Associated data