Beneficial Cardiac Effects of Caloric Restriction Are Lost with Age in a Murine Model of Obesity
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Obesity is associated with increased diastolic stiffness and myocardial steatosis and dysfunction. The impact of aging on the protective effects of caloric restriction (CR) is not clear. We studied 2-month (younger) and 6–7-month (older)-old ob/ob mice and age-matched C57BL/6J controls (WT). Ob/ob mice were assigned to diet ad libitum or CR for 4 weeks. We performed echocardiograms, myocardial triglyceride assays, Oil Red O staining, and measured free fatty acids, superoxide, NOS activity, ceramide levels, and Western blots. In younger mice, CR restored diastolic function, reversed myocardial steatosis, and upregulated Akt phosphorylation. None of these changes was observed in the older mice; however, CR decreased oxidative stress and normalized NOS activity in these animals. Interestingly, myocardial steatosis was not associated with increased ceramide, but CR altered the composition of ceramides. In this model of obesity, aging attenuates the benefits of CR on myocardial structure and function.
KeywordsObesity Caloric restriction Steatosis Lipotoxicity Diastolic dysfunction
The authors are grateful for the financial support of the American Heart Association Beginning Grant-In-Aid [to L.A.B.], American Diabetes Association [to L.A.B.], and the National Institutes of Health [5T32HL007227 to V.L.W]. There are no relationships to disclose.
- 9.Brindley, D. N., Kok, B. P. C., Kienesberger, P. C., Lehner, R., & Dyck, J. R. B. (2010). Shedding light on the enigma of myocardial lipotoxicity: the involvement of known and putative regulators of fatty acid storage and mobilization. American Journal of Physiology, Endocrinology and Metabolism, 298, E897–E908.CrossRefGoogle Scholar
- 15.Aronis, A., Madar, Z., & Tirosh, O. (2005). Mechanism underlying oxidative stress-mediated lipotoxicity: exposure of J774.2 macrophages to triacylglycerols facilitates mitochondrial reactive oxygen species production and cellular necrosis. Free Radical Biology & Medicine, 38, 1221–1230.CrossRefGoogle Scholar
- 19.Listenberger, L. L., Han, X. L., Lewis, S. E., Cases, S., Farese, R. V., Ory, D. S., et al. (2003). Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 100, 3077–3082.PubMedCrossRefGoogle Scholar
- 22.Shinmura, K., Tamaki, K., Sano, M., Murata, M., Yamakawa, H., Ishida, H., et al. (2011). Impact of long-term caloric restriction on cardiac senescence: caloric restriction ameliorates cardiac diastolic dysfunction associated with aging. Journal of Molecular and Cellular Cardiology, 50, 117–127.PubMedCrossRefGoogle Scholar
- 27.Breslow, M. J., Min-Lee, K., Brown, D. R., Chacko, V. P., Palmer, D., & Berkowitz, D. E. (1999). Effect of leptin deficiency on metabolic rate in ob/ob mice. American Journal of Physiology, Endocrinology and Metabolism, 276, E443–E449.Google Scholar
- 34.Korosoglou, G., Humpert, P. M., Ahrens, J., et al. (2012). Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve. Journal of Magnetic Resonance Imaging, 35, 804–811.PubMedCrossRefGoogle Scholar