Genetic variations in PPARD and PPARGC1A determine mitochondrial function and change in aerobic physical fitness and insulin sensitivity during lifestyle intervention

Context: Mitochondrial function is associated with aerobic physical fitness and insulin sensitivity and may play an important role in the pathophysiology of type 2 diabetes. Peroxisome proliferator-activated receptor ( PPAR)delta ( gene PPARD) and PPAR gamma coactivator 1 alpha ( gene PPARGC1A) are determinants of mitochondrial function in animals and in vitro. Objective: The objective of this study was to establish whether single-nucleotide polymorphisms ( SNPs) in PPARD and PPARGC1A modulate the effect of exercise training on change in aerobic physical fitness and insulin sensitivity and whether they affect mitochondrial function in human myotubes in vitro. Setting: The study setting was the Tuebingen Lifestyle Intervention Program in a university teaching hospital. Results: After 9 months of intervention, the minor G allele of SNP rs2267668 in PPARD and the minor serine-encoding allele of the common Gly482Ser SNP in PPARGC1A were independently associated with less increase in individual anaerobic threshold ( n = 136, P = 0.002 and P = 0.005), a precise measurement of aerobic physical fitness. Moreover, individual anaerobic threshold ( +11%) and insulin sensitivity ( +4%) increased less in subjects carrying the minor alleles at both SNPs ( X/G-X/Ser), compared with homozygous carriers of the major alleles ( A/A-Gly/Gly, +120% and +40%; P < 0.0001 and P = 0.015), suggesting an additive effect of the SNPs. In addition, low skeletal muscle mitochondrial function in vitro was detected in young carriers of the G allele of the SNP rs2267668 in PPARD ( n = 19, P = 0.02). Conclusions: These data provide evidence that the rs2267668 A/G SNP in PPARD and the Gly482Ser SNP in PPARGC1A have both independent and additive effects on the effectiveness of aerobic exercise training to increase aerobic physical fitness and insulin sensitivity.