Several genetic variants of peroxisome proliferator-activated receptor-γ2 ( PPAR-γ2), a molecule known to be involved in transcription of target genes, ha ve been identified. Pro12Ala, a missense mutation in exon 2 of the gene, is high ly prevalent in Caucasian populations. Conflicting conclusions about the associa tion between this mutation and complex traits such as obesity, insulin sensitivi ty, and T2DM have been reported. We have investigated the association of PPAR- γ2 Pro12Ala polymorphism with measures of insulin sensitivity in a population o f Italian obese children (n = 200; mean age, 10.38 ±2.8 y) in whom clinical a nd biochemical analyses were performed. To estimate the insulin sensitivity stat us, the homeostasis model assessment of insulin resistance (HOMA-IR) was calcul ated in all subjects. The effect of the Pro12Ala polymorphism on quantitative va riables was tested using multiple linear regression analysis. The frequency of A la carriers was 17%, similar to that reported in other adult Caucasian populati ons. The X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with signi ficantly lower fasting insulin levels compared with Pro/Pro (p = 0.008). Consis tent with this finding, significantly lower HOMA-IR was observed in X12Ala carr iers (p = 0.023). In conclusion, our observations demonstrate that the X12Ala v ariant is significantly associated with greater insulin sensitivity in childhood obesity. Because obesity is one of the most important risk factors for cardiova scular diseases and type 2 diabetes, obese children, who are presumably at a hig her risk, may be protected from these diseases by the phenotypic effect of the A la 12 allele on insulin resistance. u001a Several genetic variants of peroxisome proliferator-activated receptor-γ2 (PPAR-γ2), a molecule known to be involved in transcription of target genes, ha ve been identified. Pro12Ala, a missense mutation in exon 2 of the gene, is high ly prevalent in Caucasian populations. Conflicting conclusions about the associaions between this mutation and complex traits such as obesity, insulin sensitivi ty, and T2DM have been reported. We have investigated the association of PPAR- γ2 Pro12Ala polymorphism with measures of insulin sensitivity in a population of To estimate the insulin sensitivity stat us, the homeostasis model assessment of insulin resistance (HOMA-IR) was calcul ated in all subjects. The effect of the Pro12Ala polymorphism on quantitative va riables was tested using multiple linear regression analysis. The frequency of A la carriers was 17%, similar to that r The X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with signi ficantly lower fasting insulin levels compared with Pro / Pro (p = 0.008). Consis tent with this finding, significantly lower HOMA-IR was observed In conclusion, our observations demonstrate that the X12Ala v ariant is significantly associated with greater insulin sensitivity in childhood obesity. One of the most important risk factors for cardiova scular diseases and type 2 diabetes , obese children, who are presumably at a hig her risk, may be protected from these diseases by the phenotypic effect of the a la 12 allele on insulin resistance. u001a