Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a nuclear transcriptional coregulator that plays a major role in the control of metabolism and mitochondrial biogenesis. We showed that a diabetes-linked single nucleotide polymorphism (SNP rs8192678) within the coding region of PPARGC1A gene (Gly482Ser) results in decreased protein stability and half-life in liver and beta-cell lines and human induced pluripotent stem cells (iPSCs) . Our mass spectrometry data suggest that degradation of the S482 variant is mediated by phosphorylation at amino acid 482 when a serine is present. A kinome screen identified three potential kinases (NEK2, MARK4 and S6K2) that can modify this site. We found that mutation of the mouse homolog at the conserved site (serine to glycine) similarly stabilized mouse PGC1A. To study the physiological consequences of this SNP, we generated whole-body homozygous glycine (G/G) , serine (S/S) and heterozygous (S/G) mice. We analyzed various metabolic parameters in male (N=10-per genotype) and female (N=8-9) mice subjected to standard chow or high fat, high fructose diet (HFHF) for 14 or 24 weeks. We found that G/G male and female mice had increased caloric intake using metabolic cages without increased body weight. Male mice on a HFHF diet carrying a glycine allele (G/G or S/G) were more resistant to insulin in an insulin tolerance test (ITT) , secreted less insulin in response to a mixed-meal challenge and had decreased glucose uptake in muscle and adipose tissue. In line in humans, non-diabetic subjects with G/G (N=20) or G/S (N=22) variants oxidize more fat while those with S/S variant (N=6) oxidize more carbohydrate over 6-hours following the ingestion of a high-fat meal (68% fat, 18% carbohydrate) .
In summary, these results demonstrate that differences in PGC1A stability associated with phosphorylation at site 482 may lead to differences in glucose and fat metabolism, which could explain the link between this SNP and metabolic diseases.
M.Galipeau: None. M.Faraj: None. M.Oeffinger: None. F.C.Lynn: None. R.A.Screaton: None. T.Alquier: None. J.L.Estall: None. N.Jouvet: None. E.Courty: None. R.Vandenbeek: None. N.P.Khan: None. K.Bouyakdan: None. C.Nian: None. C.Iorio: None. D.D.Scott: None.
CIHR (PJT-148771) CIHR (PJT-168853)