Metabolomics Uncovers Robust Effect of Metabolic Syndrome on Major Cardiac Glucose Pathways and Byproducts

The cardiac specific energy metabolism processes in high-fat-diet-induced metabolic syndrome (MetS) are far from clear. We aim to establish and compare the myocardial metabolite profiles for MetS and lean-diet control swine. Our mass spectrometry-derived myocardial metabolite catalogs and their interpretation as a computational nonnegative matrix factorization (NMF) problem reveal MetS specific signatures, exposing unexpected alterations in fatty acid oxidation, glycolysis, gluconeogenesis, and glycogen accumulation. A contrasting enrichment in the transcription factor YY1 O-GlcNAcylation and correlation with GSK3ß and glycogen synthase 1 activity uncovers hexosamine pathway involvement that downregulates myocardial glycogen accumulation in MetS. While glycogen, fatty acids, and glucose oxidation metabolites and intermediates are low in MetS compared to the lean controls, the ketone body availability is elevated, suggesting a shift in fuel utilization and availability in MetS. Our metabolomics-NMF approach and the swine disease model could unveil novel pathways and subsequent targets for prevention and treatment of cardiac damage in MetS patients.