PPARGC1A coding variation may initiate impaired NEFA clearance during glucose challenge.
OBJECTIVE
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.


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<or=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
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.
Franks
P W
PW
Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden. paul.franks@medicin.umu.se
Ekelund
U
U
Brage
S
S
Luan
J
J
Schafer
A J
AJ
O'Rahilly
S
S
Barroso
I
I
Wareham
N J
NJ
D000273:Adipose Tissue / Q000033:anatomy & histology; D000328:Adult; D019943:Amino Acid Substitution; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
D005230:Fatty Acids, Nonesterified; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors