A Ketogenic Diet Alters Mtor Activity, Systemic Metabolism And Potentially Prevents Collagen Degradation Associated With Chronic Alcohol Consumption In Mice

Abstract

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- infammatory 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 infammatory state. Thus, a relevant question that remains is what efect 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 efect of alcohol and a KD on the phosphorylation of the mTORC1 target p70S6K, systemic metabolism as well as the redox- and infammatory 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 fow cytometry. Results Mice fed a KD exhibited signifcant 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 profling 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 infuence that a KD alongside alcohol intake can exert on not just mTOR, but also their efect on metabolic reprogramming and the redox state