PPARGC1A coding variation may initiate impaired NEFA clearance during glucose challenge

Aims/hypothesis The peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein, encoded by the PPARGC1A gene, transcriptionally activates a complex pathway of lipid and glucose metabolism and is expressed primarily in tissues of high metabolic activity such as liver, heart and exercising oxidative skeletal muscle fibre. Ppargc1a -null mice develop systemic dyslipidaemia and hepatic steatosis. In humans, NEFAs downregulate PPARGC1A expression in skeletal muscle. Furthermore, a common non-synonymous coding variant at PPARGC1A (Gly482Ser, rs8192678) is associated with decreased PPARGC1A mRNA levels and increased type 2 diabetes risk. Materials and methods In a population-based sample of 691 healthy middle-aged Europids we assessed whether Gly482Ser is associated with levels of NEFA when fasting and in response to an oral glucose challenge. We also assessed the potential effect-modifying role of adipose tissue mass on these phenotypes. Results After adjustment for age, sex, fat mass and fat-free mass, the Ser482 allele associated with higher NEFA at 30 min and 2 h and with NEFA AUC (all values p ≤ 0.02). Furthermore, suggestive evidence of interaction between fat mass and Gly482Ser was observed for fasting NEFA ( p = 0.059). After stratification by level of obesity, genotype associations were observed in the obese for fasting NEFA ( p = 0.028) and NEFA at 30 min ( p = 0.013) and 2 h ( p = 0.002), and with NEFA AUC ( p = 0.005), but no significant associations were observed in lean individuals (all values p > 0.6). Conclusions/interpretation Our observations indicate that NEFA clearance is blunted following a glucose load in carriers of the PPARCG1A Ser482 allele. This association is augmented by obesity.