Ketogenic diet administration to mice after a high-fat-diet regimen promotes weight loss, glycemic normalization and induces adaptations of ketogenic pathways in liver and kidney - Archive ouverte HAL Access content directly
Journal Articles Molecular metabolism Year : 2022

Ketogenic diet administration to mice after a high-fat-diet regimen promotes weight loss, glycemic normalization and induces adaptations of ketogenic pathways in liver and kidney

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Abstract

OBJECTIVE: The ketogenic diet (KD), characterized by very limited dietary carbohydrate intake and used as nutritional treatment for GLUT1-deficiency syndromes and pharmacologically refractory epilepsy, may promote weight loss and improve metabolic fitness, potentially alleviating the symptoms of osteoarthritis. Here, we have studied the effects of administration of a ketogenic diet in mice previously rendered obese by feeding a high fat diet (HFD) and submitted to surgical destabilization of the medial meniscus to mimic osteoarthritis. METHODS: 6-weeks old mice were fed an HFD for 10 weeks and then switched to a chow diet (CD), KD or maintained on a HFD for 8 weeks. Glycemia, β-hydroxybutyrate (BHB), body weight and fat mass were compared among groups. In liver and kidney, protein expression and histone post-translational modifications were assessed by Western blot, and gene expression by quantitative Real-Time PCR. RESULTS: After a 10 weeks HDF feeding, administration for 8 weeks of a KD or CD induced a comparable weight loss and decrease in fat mass, with better glycemic normalization in the KD group. Histone β-hydroxybutyrylation, but not histone acetylation, was increased in the liver and kidney of mice fed the KD and the rate-limiting ketogenic enzyme HMGCS2 was upregulated - at the gene and protein level - in liver and, to an even greater extent, in kidney. KD-induced HMGCS2 overexpression may be dependent on FGF21, whose gene expression was increased by KD in liver. CONCLUSIONS: Over a period of 8 weeks, KD is more effective than a chow diet to induce metabolic normalization. Besides acting as a fuel molecule, BHB may exert its metabolic effects through modulation of the epigenome - via histone β-hydroxybutyrylation - and extensive transcriptional modulation in liver and kidney.
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Dates and versions

inserm-03833167 , version 1 (28-10-2022)

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S. Nasser, T. Solé, N. Vega, T. Thomas, A. Balcerczyk, et al.. Ketogenic diet administration to mice after a high-fat-diet regimen promotes weight loss, glycemic normalization and induces adaptations of ketogenic pathways in liver and kidney. Molecular metabolism, 2022, 65, pp.101578. ⟨10.1016/j.molmet.2022.101578⟩. ⟨inserm-03833167⟩
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