A ketogenic diet alters mTOR activity, systemic metabolism and potentially prevents collagen degradation associated with chronic alcohol consumption in mice

INTRODUCTION: A ketogenic diet (KD), which is a high fat, low carbohydrate diet has been shown to inhibit the mammalian target of rapamycin (mTOR) pathway and alter the redox state. Inhibition of the mTOR complex has been associated with the attenuation and alleviation of various metabolic and- inflammatory diseases such as neurodegeneration, diabetes, and metabolic syndrome. Various metabolic pathways and signalling mechanisms have been explored to assess the therapeutic potential of mTOR inhibition. However, chronic alcohol consumption has also been reported to alter mTOR activity, the cellular redox- and inflammatory state. Thus, a relevant question that remains is what effect chronic alcohol consumption would have on mTOR activity and overall metabolism during a KD-based intervention. OBJECTIVES: The aim of this study was to evaluate the effect of alcohol and a KD on the phosphorylation of the mTORC1 target p70S6K, systemic metabolism as well as the redox- and inflammatory state in a mouse model. METHODS: Mice were fed either a control diet with/without alcohol or a KD with/without alcohol for three weeks. After the dietary intervention, samples were collected and subjected towards western blot analysis, multi-platform metabolomics analysis and flow cytometry. RESULTS: Mice fed a KD exhibited significant mTOR inhibition and reduction in growth rate. Alcohol consumption alone did not markedly alter mTOR activity or growth rate but moderately increased mTOR inhibition in mice fed a KD. In addition, metabolic profiling showed alteration of several metabolic pathways as well as the redox state following consumption of a KD and alcohol. A KD was also observed to potentially prevent bone loss and collagen degradation associated with chronic alcohol consumption, as indicated by hydroxyproline metabolism. CONCLUSION: This study sheds light on the influence that a KD alongside alcohol intake can exert on not just mTOR, but also their effect on metabolic reprogramming and the redox state. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11306-023-02006-w.