AIMS/HYPOTHESIS: The objectives of the present investigation were to examine: 1) whether a Pro115Gln variant in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with juvenile-onset obesity among Danish Caucasianmen and 2) whether the relation of a Pro12Ala polymorphism in PPAR-gamma2 with BMI and long-term weight regulation differ between lean and obese subjects within the same cohort. METHODS: The Pro115Gln and Pro112Ala variants were examined using PCR and RFLP in a group of 752 subjects with a Body Mass Index (BMI) of 31.0 kg/m2 or more and in 869 non-obese control subjects. RESULTS: We did not find Pro115Gln in any of the 1621 male subjects we examined. Among the males with juvenile-onset obesity, the allelic frequency of the Pro12Ala polymorphism was 14% (95% confidence interval: 12-16%) compared with 16% (14-17%) among the non-obese control subjects (NS). Heterozygosity of the codon 12 variant was not associated with differences in BMI or changes in body weight regulation during follow up in lean or obese subjects. In the group of obese subjects, 21 homozygous Ala12Ala carriers had, however, a higher BMI (38.9 +/- 5.4 kg/m2 (means +/- SD) vs 35.5 +/- 5.5 kg/ m2, p = 0.008) and a higher weight gain (0.27 +/- 0.24 kg x m(-2) x year(-1) vs 0.10 +/- 0.24 kg x m(-2) x year(-1), p = 0.004), compared with wild-type carriers. Moreover, within the control group of 869 men the 14 homozygous carriers of the variant had a lower BMI (24.4 +/- 2.7 kg/m2 vs 26.2 +/- 3.7 kg/m2, p = 0.005) and a slower increase in BMI (0.11 +/- 0.11 kg x m(-2) x year(-1) vs 0.17 +/- 0.11 kg x m(-2) x year(-1), p = 0.002) compared with wild-type carriers. CONCLUSION/INTERPRETATION: The codon 12 variant of PPAR-gamma2 is not intrinsically associated with juvenile obesity. The variant may in its homozygous form interact, however, with various combinations of genetic and environmental factors in lean and obese subjects to cause divergent modulating effects on BMI and long-term body weight control.