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Genetic Variations in PPARD and PPARGC1A Determine Mitochondrial Function and Change in Aerobic Physical Fitness and Insulin Sensitivity during Lifestyle Intervention

Department of Internal Medicine (N.S., C.T., H.S., F.M., A.F., H.-U.H.), Division of Endocrinology, Metabolism, Pathobiochemistry, and Clinical Chemistry, Section on Experimental Radiology (J.M., F.S.), Department of Internal Medicine (C.V., A.N.), Division of Sports Medicine, University of Tübingen, D-72076 Tübingen, Germany; and Department of Medicine (M.L.), University of Kuopio, KI-70210 Kuopio, Finland

Address all correspondence and requests for reprints to: Norbert Stefan, M.D., Department of Internal Medicine, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. E-mail: norbert.stefan{at}med.uni-tuebingen.de.

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)- (gene PPARD) and PPAR coactivator 1 (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.

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