Regulation of Myocardial Lipid Accumulation in the Development of Obesity
Authors: Zhou Redemptor , Poudel Arya , Fillmore Natasha 
Published: May 2024

Energy metabolism is important in the development of heart disease, which is the leading cause of death worldwide. The importance of energy metabolism in disease is becoming even more clear with the rise in obesity, metabolic diseases, and the recognition that they all fit together as with the recent offcial report of a new syndrome named Cardiovascular-Kidney-Metabolic (CKM) Syndrome. A complete understanding of myocardial lipid storage and subsequent utilization of lipids is essential to understanding the impact of these metabolic diseases in the heart and on the development of cardiac dysfunction and hypertrophy. In this study we investigate how the heart controls fuel storage by taking advantage of the impact of the transcription factor peroxisome proliferator activated receptor α (PPARα) on 1) fatty acid metabolism and lipid accumulation, 2) its key role in sex differences in cardiac hypertrophy which we previously reported, and 3) the regulation of lipid droplets. It is controversial whether a decline in myocardial PPARα mediates cardiac hypertrophy and whether it increases or reduces lipid accumulation. Using our tamoxifen inducible cardiac-specific PPARα knockout mouse (cPPAR−/−) we see less cardiac lipid accumulation in response to a 5 week high fat diet. Our data indicate that this difference in triglyceride levels is present in both males and females. Importantly, this is not driven by a difference in fatty acid supply to these hearts. Serum fatty acid levels are not lower in cPPAR−/− vs Control mice fed a high fat diet. Further, we have not observed a difference in high fat diet induced body weight gain between cPPAR−/− and Control mice. We have begun to examine how these differences in high fat diet-induced lipid accumulation correlate with cardiac hypertrophy by looking at heart weight normalized to tibia length. While we did not expect 5 weeks of a high fat diet to induce cardiac hypertrophy, it is possible that the difference in cardiac lipid storage in the cPPAR−/− hearts could impact this. This measurement did not indicate a difference in cardiac hypertrophy between high fat diet fed cPPAR−/− and Control mice. We are utilizing this mouse as a model to investigate the regulation of lipid droplets and the lipid droplet proteome. So far, our results are indicating that the regulation of lipid droplet proteins is not affected in a uniform manner. For example, our data is suggesting that the expression of different members of the perilipin family are affected in distinct ways. Overall, these data indicate that a reduction in cardiac PPARα protects against obesity induced cardiac lipid accumulation. Going forward, it will be interesting to see how these changes occur in relation to the lipid droplet proteome and whether any changes that occur differentially in males vs female may be involved in sex differences in cardiac hypertrophy. Better understanding these factors will be essential for the development of safe and effective future therapies for CKM syndrome and other cardiovascular diseases. ND-EPSCoR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.