Tissue Level Diet and Sex-by-Diet Interactions Reveal Unique Metabolite and Clustering Profiles Using Untargeted Liquid Chromatography–Mass Spectrometry on Adipose, Skeletal Muscle, and Liver Tissue in C57BL6/J Mice

Dietary intervention
is commonly used for weight loss or to improve
health, as diet-induced obesity increases the risk of developing type
2 diabetes, hypertension, cardiovascular disease, stroke, osteoarthritis,
and certain cancers. Various dietary patterns are associated with
effects on health, yet little is known about the effects of diet at
the tissue level. Using untargeted metabolomics, this study aimed
to identify changes in water-soluble metabolites in C57BL/6J males
and females fed one of five diets (Japanese, ketogenic, Mediterranean,
American, and standard mouse chow) for 7 months. Metabolite abundance
was examined in liver, skeletal muscle, and adipose tissue for sex,
diet, and sex-by-diet interaction. Analysis of variance (ANOVA) suggests
that liver tissue has the most metabolic plasticity under dietary
changes compared with adipose and skeletal muscle. The ketogenic diet
was distinguishable from other diets for both males and females according
to partial least-squares discriminant analysis. Pathway analysis revealed
that the majority of pathways affected play an important role in amino
acid metabolism in liver tissue. Not surprisingly, amino acid profiles
were affected by dietary patterns in skeletal muscle. Few metabolites
were significantly altered in adipose tissue relative to skeletal
muscle and liver tissue, indicating that it was largely stable, regardless
of diet alterations. The results of this study revealed that the ketogenic
diet had the largest effect on physiology, particularly for females.
Furthermore, metabolomics analysis revealed that diet affects metabolites
in a tissue-specific manner and that liver was most sensitive to dietary
changes.