Impact of High-Fat Diet-induced Metabolic Dysfunction-associated Steatotic Liver Disease on Heart, Kidney, and Skeletal Muscle Metabolomes in Wild-Type Mice

<b>Background:</b> Metabolic dysfunction-associated steatotic liver disease (MASLD) can be recapitulated in mice fed a high-fat diet. The development of MASLD and the diet <i>per se</i> can both perturb metabolism in key extrahepatic tissues such as the heart, kidney, and skeletal muscle. To date, these alterations have not been well described in this animal model of diet-induced MASLD. <b>Methodology:</b> Male C57BL/6J mice were fed either standard (SC, <i>n</i> = 12) or high-fat chow (HF, <i>n</i> = 11) for 18 weeks. Metabolites were extracted from the heart, kidney, and skeletal muscle and analyzed by ¹H nuclear magnetic resonance (NMR) spectroscopy, along with multivariate and univariate statistical analyses. <b>Results:</b> Kidney metabolite profiles exhibited the largest differences between HF and SC diets, followed by those of skeletal muscle and then the heart. Some alterations were common across all tissues, namely decreased trimethylamine and elevated levels of linoleic acid and polyunsaturated fatty acids in HF compared to SC (<i>p</i> < 0.05 for all three metabolites). Overall, the metabolite variations were consistent with shifts in carbohydrate and lipid substrate selection for oxidation, increased tissue stress in the heart and kidneys, and altered choline metabolism. These findings may serve as additional important descriptors of MASLD onset and progression.