Abstract
Ketogenic diets, which are high in fat, hold therapeutic promises in obesity and type 2 diabetes and are to be carefully studied in their early stages on healthy mouse models. This study evaluated the physiological, biochemical, histological, and genetic impacts of a Moringa oleifera-supplemented ketogenic meal replacement (KMR) compared with a commercial non-ketogenic meal replacement (CMR) and standard chow in female C57BL/6J mice (n = 8/group) over 20 weeks. Despite similar caloric intake, KMR-fed mice exhibited ~ 30% lower weight gain than both control and CMR groups, highlighting the role of macronutrient composition over energy content. Insulin sensitivity was preserved across groups, with KMR maintaining fasting glucose, insulin, and HOMA-IR < 0.4. KMR promoted favorable lipid remodeling, including elevated HDL cholesterol (128 ± 6 mg/dL), reduced LDL cholesterol (25 ± 2 mg/dL), and the lowest non-HDL cholesterol, yielding the most favorable HDL: LDL ratio. Liver enzyme analysis revealed hepatoprotective effects in KMR, contrasting with elevated ALT and AST in CMR. Renal biomarkers and the histological observations indicated mild disorder in kidney functions across CMR and KMR groups. At the molecular level, KMR upregulated ketogenesis genes (Hmgcs2, Bdh1), mitochondrial regulators (Sirt3, Fgf21), and the anti-inflammatory cytokine IL10. Conversely, CMR downregulated Bdh1, Fgf21, and IL10 while exerting negligible or nonsignificant effects on Hmgcs2 and Sirt3. Collectively, KMR attenuated weight gain and improved lipid metabolism maintaining insulin and blood glucose levels. This supports its effective dietary management for type 2 diabetes. However, given the observed histological changes, further long-term studies are recommended to confirm the safety of the ketogenic diet on organ tissues.