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

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.

doi:10.64898/2026.10.16.759626

bioRxiv · 10.64898/2026.10.16.759626

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

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.

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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.

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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.. 2026-10-22. The PGC-1α Gly482Ser rs8192678 SNP reprograms oxidative metabolism to favor energy storage in females. https://doi.org/10.64898/2026.10.16.759626

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