Western Diet Causes Heart Failure With Reduced Ejection Fraction and Metabolic Shifts After Diastolic Dysfunction and Novel Cardiac Lipid Derangements

[Display omitted] •WD leads to impaired diastolic function and impaired systolic function with reduced ejection fraction.•WD induces novel derangements of cardiac lipid dynamics owing to reduced lipase content that are distinct from other models of diabetes and insulin resistance and congestive heart failure.•Despite eventual up-regulation of the key enzyme for ketone oxidation (BDH1) during WD, in the absence of reduced long-chain fatty acid oxidation during nutrient overload there is no increase in ketone oxidation.•With eventual HFrEF due to WD, cardiac use of exogenous glucose becomes altered owing to reduced GLUT4 expression. Western diet (WD) impairs glucose tolerance and cardiac lipid dynamics, preceding heart failure with reduced ejection fraction (HFrEF) in mice. Unlike diabetic db/db mice with high cardiac triglyceride (TG) and rapid TG turnover, WD mice had high TG but slowed turnover, reducing lipolytic PPAR⍺ activation. WD deranged cardiac TG dynamics by imbalancing synthesis and lipolysis, with low cardiac TG lipase (ATGL), low ATGL co-activator, and high ATGL inhibitory peptide. By 24 weeks of WD, hearts shifted from diastolic dysfunction to diastolic dysfunction with HFrEF with decreases in GLUT4 and exogenous glucose oxidation and elevated β-hydroxybutyrate dehydrogenase 1 without increasing ketone oxidation.