Loss-of-function G6PD variant moderated high-fat diet-induced obesity, adipocyte hypertrophy, and fatty liver in male rats

Authors: Shun Matsumura, Christina Signoretti, Samuel Fatehi, Bat Ider Tumenbayar, Catherine D'Addario, Erik Nimmer, Colin Thomas, Trisha Viswanathan, Alexandra Wolf, Victor Garcia, Petra Rocic, Yongho Bae, Sm Shafiqul Alam, Sachin A Gupte

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Obesity contributes to liver and cardiovascular diseases, but the underlying multi‑organ mechanisms remain unclear. This study shows that glucose‑6‑phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway, drives obesity‑related metabolic reprogramming in visceral fat, liver, and aorta during long‑term high‑fat diet feeding in rats. Rats carrying a loss‑of‑function Mediterranean G6PD variant (G6PDS188F) exhibited reduced weight gain, inflammation, adipocyte hypertrophy, fatty liver, and aortic stiffening, along with increased expression of the obesity‑suppressing gene Magel2. These findings identify G6PD as a central regulator of diet‑induced obesity and its associated metabolic and cardiovascular complications

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