Context: We recently demonstrated that single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor gene (PPARD), i.e. rs1053049, rs6902123, and rs2267668, affect the improvement of mitochondrial function, aerobic physical fitness, and insulin sensitivity by lifestyle intervention (LI).

Objective: To determine whether the aforementioned PPARD SNPs influence the change in body composition and ectopic fat storage during LI.

Design: 156 subjects at an increased risk for type 2 diabetes were genotyped for rs1053049, rs6902123, and rs2267668 and participated in a LI program. Body fat depots, ectopic liver fat, and muscle volume of the leg were quantified using magnetic resonance spectroscopy and imaging.

Results: With regard to body composition, carriers of the minor SNP alleles displayed reduced responses to LI, i.e. LI-induced reduction in adipose tissue mass (non-visceral adipose tissue: rs1053049, p=0.02; rs2267668, p=0.04; visceral adipose tissue: rs1053049, p=0.0and in hepatic lipids (rs1053049, p=0.04; rs6902123, p=0.001; independent of changes in adiposity) as well as LI-induced increase in relative muscle volume of the leg (rs1053049, p=0.003; rs2267668 p=0.009) were less pronounced in homo- and heterozygous carriers of the minor alleles as compared to homozygous carriers of the major alleles.

Conclusion: SNPs rs1053049, rs6902123, and rs2267668 in PPARD affect LI-induced changes in overall adiposity, hepatic fat storage, and relative muscle mass. Our findings provide a mechanistic explanation for the involvement of these genetic variations in the development of insulin resistance and type 2 diabetes.