The PGC-1α Gly482Ser rs8192678 SNP reprograms oxidative metabolism to favor energy storage in females

Authors

Galipeau, M., Jouvet, N., Schoumacher, M., Courty, E., Vandenbeek, R., Gunes, A., Braud, M., Fourgeux, C., Poschmann, J., C. Lynn, F., Faraj, M., Estall, J. L.

Abstract

The Gly482Ser SNP (rs8192678) in the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) gene has been associated with obesity, type 2 diabetes and other human metabolic diseases. In this study, we found that human iPSCs carrying a serine risk allele had reduced respiratory capacity, and individuals living with overweight or obesity homozygous for the serine allele (S/S) exhibited a preference for carbohydrate oxidation following a high-fat meal. Using a PGC-1Ser481Gly knock-in mouse model, we performed metabolic phenotyping of male and female mice carrying the three genotypes (G/G, S/G, S/S) under acute nutritional challenges (chow, fasting and high-fat high-sugar (HFHS) feeding) and chronic HFHS feeding. S/S females were heavier and showed a trend toward an increased respiratory exchange ratio (RER) during fasting, with greater weight gain and fat mass following chronic HFHS feeding. Transcriptomic analyses revealed tissue-specific reprogramming of mitochondrial oxidative pathways, that were downregulated in subcutaneous adipose tissue and liver while upregulated in muscle, with the strongest effects observed in S/S females. Together, these findings provide in vivo evidence that this SNP reprograms whole-body oxidative metabolism, with a net effect of favoring carbohydrate oxidation and energy conservation, particularly in females.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 23 Oct 2026.

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