PPARGC1A coding variation may initiate impaired NEFA clearance during glucose challenge
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.
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).
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.
- Spiegelman BM, Puigserver P, Wu Z (2000) Regulation of adipogenesis and energy balance by PPARgamma and PGC-1. Int J Obes Relat Metab Disord 24(Suppl 4):S8–S10
- Soyal S, Krempler F, Oberkofler H, Patsch W (2006) PGC-1alpha: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes. Diabetologia 49:1477–1488 CrossRef
- Mootha VK, Lindgren CM, Eriksson KF et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273 CrossRef
- Ling C, Poulsen P, Carlsson E et al (2004) Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. J Clin Invest 114:1518–1526 CrossRef
- Barroso I, Luan J, Sandhu M et al (2006) Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes. Diabetologia 49:501–505 CrossRef
- Muller YL, Bogardus C, Pedersen O, Baier L (2003) A Gly482Ser missense mutation in the peroxisome proliferator-activated receptor gamma coactivator-1 is associated with altered lipid oxidation and early insulin secretion in Pima Indians. Diabetes 52:895–898
- Ek J, Andersen G, Urhammer SA et al (2001) Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to type II diabetes mellitus. Diabetologia 44:2220–2226 CrossRef
- Esterbauer H, Oberkofler H, Linnemayr V et al (2002) Peroxisome proliferator-activated receptor-gamma coactivator-1 gene locus: associations with obesity indices in middle-aged women. Diabetes 51:1281–1286
- Semple RK, Crowley VC, Sewter CP et al (2004) Expression of the thermogenic nuclear hormone receptor coactivator PGC-1alpha is reduced in the adipose tissue of morbidly obese subjects. Int J Obes Relat Metab Disord 28:176–179 CrossRef
- Barroso I, Luan J, Middelberg RP et al (2003) Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biol 1:E20 CrossRef
- Lillioja S, Nyomba BL, Saad MF et al (1991) Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians. J Clin Endocrinol Metab 73:866–876 CrossRef
- Hoeks J, Hesselink MK, Russell AP et al (2006) Peroxisome proliferator-activated receptor-gamma coactivator-1 and insulin resistance: acute effect of fatty acids. Diabetologia 49:2419–2426 CrossRef
- PPARGC1A coding variation may initiate impaired NEFA clearance during glucose challenge
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- Author Affiliations
- 1. Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden
- 2. MRC Epidemiology Unit, Cambridge, UK
- 3. Incyte, Porter Drive, Palo Alto, CA, USA
- 4. Departments of Clinical Biochemistry and Medicine, Addenbrooke’s Hospital, Cambridge, UK
- 5. Metabolic Disease Group, The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK