The Pro12Ala variant at the peroxisome proliferator-activated receptor γ gene and change in obesity-related traits in the Diabetes Prevention Program

Aims/hypothesis Peroxisome proliferator-activated receptor. (PPAR.), encoded by the PPARG gene, regulates insulin sensitivity and adipogenesis, and may bind polyunsaturated fatty acids (PUFA) and thiazolidinediones in a ligand-dependent manner. The PPARG proline for alanine substitution at position 12 (Pro12Ala polymorphism) has been related with obesity directly and via interaction with PUFA. Methods We tested the effect-modifying role of Pro12Ala on the 1 year change in obesity-related traits in a randomised clinical trial of treatment with metformin (n= 989), troglitazone (n= 363) or lifestyle modification (n= 1,004) vs placebo (n= 1,000) for diabetes prevention in high- risk individuals. Results At baseline, Ala12 carriers had larger waists (p< 0.001) and, in a subset, more subcutaneous adipose tissue (SAT; lumbar 2/ 3; p= 0.04) than Pro12 homozygotes. There was a genotype- by- intervention interaction on 1- year weight change (p= 0.01); in the placebo arm, Pro12 homozygotes gained weight and Ala12 carriers lost weight (p= 0.001). In the metformin and lifestyle arms, weight loss occurred across genotypes, but was greatest in Ala12 carriers (p< 0.05). Troglitazone treatment induced weight gain, which tended to be greater in Ala12 carriers (p= 0.08). In the placebo group, SAT (lumbar 2/3, lumbar 4/5) decreased in Ala12 allele carriers, but was unchanged in Pro12 homozygotes (p <= 0.005). With metformin treatment, SAT decreased independently of genotype. In the lifestyle arm, SAT (lumbar 2/ 3) reductions occurred across genotypes, but were greater in Ala12 carriers (p= 0.03). A genotype-by-PUFA intake interaction on reduction in visceral fat (lumbar 4/ 5; p= 0.04) was also observed, which was most evident with metformin treatment (p< 0.001). Conclusions/ interpretation Within the Diabetes Prevention Program, the Ala12 allele influences central obesity, an effect which may differ by treatment group and dietary PUFA intake (ClinicalTrials.gov ID no: NCT00004992).