摘要:SummaryThe response of vital organs to different types of nutrition or diet is a fundamental question in physiology. We examined the cardiac response to 4 weeks of high-fat diet in mice, measuring cardiac metabolites and mRNA. Metabolomics showed dramatic differences after a high-fat diet, including increases in several acyl-carnitine species. The RNA-seq data showed changes consistent with adaptations to use more fatty acid as substrate and an increase in the antioxidant protein catalase. Changes in mRNA were correlated with changes in protein level for several highly responsive genes. We also found significant sex differences in both metabolomics and RNA-seq datasets, both at baseline and after high fat diet. This work reveals the response of a vital organ to dietary intervention at both metabolomic and transcriptomic levels, which is a fundamental question in physiology. This work also reveals significant sex differences in cardiac metabolites and gene expression.Graphical abstractDisplay OmittedHighlights•Cardiac gene expression shows adaptive changes after short-term high-fat diet•Cardiac metabolomics indicate mitochondrial dysfunction after high-fat diet•Metabolites and gene expression show significant sex differences at baseline•There are significant sex differences in the changes caused by high-fat dietPathophysiology; Human metabolism; Metabolomics; Transcriptomics