Dysfunctional Cardiac Fatty Acid Metabolism in Cystathionine‐beta‐Synthase +/‐ Mice with Obesity

Abstract

Obesity‐related cardiac lipid accumulation is associated with toxicity and dysfunction. Cysteine is required for the synthesis of the antioxidant glutathione, supplied by the transsulfuration of homocysteine by cystathionine‐beta‐synthase (Cbs). Cbs+/‐ mice with diet‐induced obesity have reduced cardiac glutathione, and greater glucose intolerance and cardiac lipotoxicity. Our objective was to determine the functional effects and mechanisms of cardiac lipotoxicity in Cbs+/‐ mice with diet‐induced obesity. Cbs+/‐ and Cbs+/+ mice were fed a control‐diet (CD) or a high‐fat diet (HFD) from weaning for 20 weeks. Cbs+/‐ mice fed CD had less visceral adiposity compared to Cbs+/+ mice. Ex vivo working heart assessments revealed greater palmitate oxidation in mice fed the HFD than CD. Independent of diet, Cbs+/‐ mice had reduced palmitate oxidation compared to Cbs+/+ mice. Cbs+/‐ mice had larger hearts and more arachidonic acid (AA) and docosahexaenoic acid (DHA) concentrations in the heart than Cbs+/+ mice. Mice fed the HFD had higher AA, but lower DHA concentrations in the heart than mice fed the CD; effects greatest in Cbs+/‐ mice. A lower ratio of phosphorylated‐AMPKα/AMPKα expression was observed in Cbs+/‐ than Cbs+/+ mice, and this occurred to a greater extent in those fed the HFD. Cbs+/‐ mice with diet‐induced obesity have altered cardiac fatty acid metabolism and larger hearts, further supporting a role for Cbs in obesity‐related cardiac lipotoxicity.Supported by NSERC and CIHR