Dietary sugar type determines the response to protein restriction in females, but not males

Sonsalla, M. M.; Cole, M.; Johnson, M.; Cai, S.; Virnig, B.; Trebil, A.; Babygirija, R.; Illiano, J.; Vertein, D.; Liu, Y.; Grunow, I.; Knopf, B. A.; Schlorf, S.; Rigby, M.; Yeh, C.-Y.; Green, C. L.; Harris, D. A.; Puglielli, L.; Lamming, D. W.

doi:10.64898/2026.08.18.745207

bioRxiv · 10.64898/2026.08.18.745207

Dietary sugar type determines the response to protein restriction in females, but not males

Sonsalla, M. M.·Cole, M.·Johnson, M.·Cai, S.·Virnig, B.·Trebil, A.·Babygirija, R.·Illiano, J.·Vertein, D.·Liu, Y.·Grunow, I.·Knopf, B. A.·Schlorf, S.·Rigby, M.·Yeh, C.-Y.·Green, C. L.·Harris, D. A.·Puglielli, L.·Lamming, D. W.

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Abstract

Low protein (LP) diets improve metabolic health in rodents and humans. In rodents, LP diets are typically implemented by replacing protein with carbohydrates like sucrose or cornstarch, keeping diets isocaloric. However, humans can choose from many different types of carbohydrate, and how dietary carbohydrate quality - the precise composition of the dietary sugars - impacts the response to dietary protein remains largely unexplored. Here, mice were fed control (21% protein) or LP (7% protein) diets with four different carbohydrate sources: sucrose, a 1:1 glucose/fructose mixture, glucose, or fructose. While LP diets improved metabolic health across all groups in male mice, carbohydrate quality also significantly altered specific health outcomes, with fructose-fed mice having the lowest body weight and adiposity of all control diets. In female mice, responses to LP diets were influenced by carbohydrate quality, with certain sugars inducing a stronger metabolic response to LP diets than previously seen. Finally, in female APP/PS1 mice, a model of Alzheimer's disease, we find that although LP diets reduce A-beta; plaque burden irrespective of carbohydrate type, dietary sugar type does influence spatial memory. Together, these results demonstrate that while dietary protein is a critical determinant of metabolic and neurological health, carbohydrate quality influences these outcomes in a sex-specific manner.

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Sonsalla, M. M., Cole, M., Johnson, M., Cai, S., Virnig, B., Trebil, A., Babygirija, R., Illiano, J., Vertein, D., Liu, Y., Grunow, I., Knopf, B. A., Schlorf, S., Rigby, M., Yeh, C.-Y., Green, C. L., Harris, D. A., Puglielli, L., Lamming, D. W.. 2026-08-23. Dietary sugar type determines the response to protein restriction in females, but not males. https://doi.org/10.64898/2026.08.18.745207

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