Beneficial Cardiac Effects of Caloric Restriction Are Lost with Age in a Murine Model of Obesity

  • Majd AlGhatrif
  • Vabren L. Watts
  • Xiaolin Niu
  • Marc Halushka
  • Karen L. Miller
  • Konrad Vandegaer
  • Djahida Bedja
  • Karen Fox-Talbot
  • Alicja Bielawska
  • Kathleen L. Gabrielson
  • Lili A. Barouch


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.


Obesity 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.


  1. 1.
    Cepeda-Valery, B., Pressman, G. S., Figueredo, V. M., & Romero-Corral, A. (2011). Impact of obesity on total and cardiovascular mortality—fat or fiction? Nature Reviews Cardiology, 8, 233–237.PubMedCrossRefGoogle Scholar
  2. 2.
    Barouch, L. A., Berkowitz, D. E., Harrison, R. W., O'Donnell, C. P., & Hare, J. M. (2003). Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation, 108, 754–759.PubMedCrossRefGoogle Scholar
  3. 3.
    Mazumder, P. K., O'Neill, B. T., Roberts, M. W., et al. (2004). Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes, 53, 2366–2374.PubMedCrossRefGoogle Scholar
  4. 4.
    Abel, E. D., Litwin, S. E., & Sweeney, G. (2008). Cardiac remodeling in obesity. Physiological Reviews, 88, 389–419.PubMedCrossRefGoogle Scholar
  5. 5.
    Barouch, L. A., Gao, D., Chen, L., et al. (2006). Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circulation Research, 98, 119–124.PubMedCrossRefGoogle Scholar
  6. 6.
    Silvani, A., Bastianini, S., Berteotti, C., Franzini, C., Lenzi, P., Lo Martire, V., et al. (2009). Sleep modulates hypertension in leptin-deficient obese mice. Hypertension, 53, 251–255.PubMedCrossRefGoogle Scholar
  7. 7.
    Buchanan, J., Mazumder, P. K., Hu, P., et al. (2005). Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology, 146, 5341–5349.PubMedCrossRefGoogle Scholar
  8. 8.
    Christoffersen, C., Bollano, E., Lindegaard, M. L. S., Bartels, E. D., Goetze, J. P., Andersen, C. B., et al. (2003). Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology, 144, 3483–3490.PubMedCrossRefGoogle Scholar
  9. 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
  10. 10.
    Park, T. S., Yamashita, H., Blaner, W. S., & Goldberg, I. J. (2007). Lipids in the heart: a source of fuel and a source of toxins. Current Opinion in Lipidology, 18, 277–282.PubMedCrossRefGoogle Scholar
  11. 11.
    Bugger, H., & Abel, E. D. (2008). Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome. Clinical Science, 114, 195–210.PubMedCrossRefGoogle Scholar
  12. 12.
    Chiu, H. C., Kovacs, A., Ford, D. A., et al. (2001). A novel mouse model of lipotoxic cardiomyopathy. Journal of Clinical Investigation, 107, 813–822.PubMedCrossRefGoogle Scholar
  13. 13.
    Boudina, S., Sena, S., O'Neill, B. T., Tathireddy, P., Young, M. E., & Abel, E. D. (2005). Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation, 112, 2686–2695.PubMedCrossRefGoogle Scholar
  14. 14.
    Boudina, S., Sena, S., Theobald, H., et al. (2007). Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes, 56, 2457–2466.PubMedCrossRefGoogle Scholar
  15. 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
  16. 16.
    Bielawska, A. E., Shapiro, J. P., Jiang, L., et al. (1997). Ceramide is involved in triggering of cardiomyocyte apoptosis induced by ischemia and reperfusion. American Journal of Pathology, 151, 1257–1263.PubMedGoogle Scholar
  17. 17.
    Kong, J. Y., Klassen, S. S., & Rabkin, S. W. (2005). Ceramide activates a mitochondrial p38 mitogen-activated protein kinase: a potential mechanism for loss of mitochondrial transmembrane potential and apoptosis. Molecular and Cellular Biochemistry, 278, 39–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Parra, V., Eisner, V., Chiong, M., et al. (2008). Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovascular Research, 77, 387–397.PubMedCrossRefGoogle Scholar
  19. 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
  20. 20.
    de Vries, J. E., Vork, M. M., Roemen, T., de Jong, Y. F., Cleutjens, J., Van Der Vusse, G., et al. (1997). Saturated but not mono-unsaturated fatty acids induce apoptotic cell death in neonatal rat ventricular myocytes. Journal of Lipid Research, 38, 1384.PubMedGoogle Scholar
  21. 21.
    Weiss, E. P., & Fontana, L. (2011). Caloric restriction: powerful protection for the aging heart and vasculature. American Journal of Physiology-Heart and Circulatory Physiology, 301, H1205–H1219.PubMedCrossRefGoogle Scholar
  22. 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
  23. 23.
    Viljanen, A. P. M., Karmi, A., Borra, R., et al. (2009). Effect of caloric restriction on myocardial fatty acid uptake, left ventricular mass, and cardiac work in obese adults. The American Journal of Cardiology, 103, 1721–1726.PubMedCrossRefGoogle Scholar
  24. 24.
    Hammer, S., Snel, M., Lamb, H. J., et al. (2008). Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function. Journal of the American College of Cardiology, 52, 1006–1012.PubMedCrossRefGoogle Scholar
  25. 25.
    Sloan, C., Tuinei, J., Nemetz, K., et al. (2011). Central leptin signaling is required to normalize myocardial fatty acid oxidation rates in caloric-restricted ob/ob mice. Diabetes, 60, 1424–1434.PubMedCrossRefGoogle Scholar
  26. 26.
    Rame, J. E., Barouch, L. A., Sack, M. N., et al. (2011). Caloric restriction in leptin deficiency does not correct myocardial steatosis: failure to normalize PPAR alpha/PGC1 alpha and thermogenic glycerolipid/fatty acid cycling. Physiological Genomics, 43, 726–738.PubMedCrossRefGoogle Scholar
  27. 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
  28. 28.
    Morricone, L., Malavazos, A. E., Coman, C., Donati, C., Hassan, T., & Caviezel, F. (2002). Echocardiographic abnormalities in normotensive obese patients: relationship with visceral fat. Obesity Research, 10, 489–498.PubMedCrossRefGoogle Scholar
  29. 29.
    Münzel, T., Afanas’ev, I. B., Kleschyov, A. L., & Harrison, D. G. (2002). Detection of superoxide in vascular tissue. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 1761–1768.PubMedCrossRefGoogle Scholar
  30. 30.
    Moens, A. L., Leyton-Mange, J. S., Niu, X., et al. (2009). Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor. Journal of Molecular and Cellular Cardiology, 47, 576–585.PubMedCrossRefGoogle Scholar
  31. 31.
    Takimoto, E., Champion, H. C., Li, M., et al. (2005). Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. The Journal of Clinical Investigation, 115, 1221–1231.PubMedGoogle Scholar
  32. 32.
    Bielawski, J., Szulc, Z. M., Hannun, Y. A., & Bielawska, A. (2006). Simultaneous quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Methods, 39, 82–91.PubMedCrossRefGoogle Scholar
  33. 33.
    Birse, R. T., & Bodmer, R. (2011). Lipotoxicity and cardiac dysfunction in mammals and Drosophila. Critical Reviews in Biochemistry and Molecular Biology, 46, 376–385.PubMedCrossRefGoogle Scholar
  34. 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
  35. 35.
    Sikka, G., Yang, R., Reid, S., et al. (2010). Leptin is essential in maintaining normal vascular compliance independent of body weight. International Journal of Obesity, 34, 203–206.PubMedCrossRefGoogle Scholar
  36. 36.
    Kaltman, A. J., & Goldring, R. M. (1976). Role of circulatory congestion in the cardiorespiratory failure of obesity. American Journal of Medicine, 60, 645–653.PubMedCrossRefGoogle Scholar
  37. 37.
    Lakatta, E. G. (1987). Do hypertension and aging have a similar effect on the myocardium? Circulation, 75, I69–I77.PubMedGoogle Scholar
  38. 38.
    Ren, J., Dong, F., Cai, G. J., Zhao, P., Nunn, J. M., Wold, L. E., et al. (2010). Interaction between age and obesity on cardiomyocyte contractile function: role of leptin and stress signaling. PLoS One, 5, e10085.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhen, J., Lu, H., Wang, X. Q., Vaziri, N. D., & Zhou, X. J. (2008). Upregulation of endothelial and inducible nitric oxide synthase expression by reactive oxygen species. American Journal of Hypertension, 21, 28–34.PubMedCrossRefGoogle Scholar
  40. 40.
    Luo, J., Xuan, Y. T., Gu, Y., & Prabhu, S. D. (2006). Prolonged oxidative stress inverts the cardiac force-frequency relation: role of altered calcium handling and myofilament calcium responsiveness. Journal of Molecular and Cellular Cardiology, 40, 64–75.PubMedCrossRefGoogle Scholar
  41. 41.
    Balaban, R. S., Nemoto, S., & Finkel, T. (2005). Mitochondria, oxidants, and aging. Cell, 120, 483–495.PubMedCrossRefGoogle Scholar
  42. 42.
    Dai, D. F., Rabinovitch, P. S., & Ungvari, Z. (2012). Mitochondria and cardiovascular aging. Circulation Research, 110, 1109–1124.PubMedCrossRefGoogle Scholar
  43. 43.
    Bakris, G. L., Bank, A. J., Kass, D. A., Neutel, J. M., Preston, R. A., & Oparil, S. (2004). Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. American Journal of Hypertension, 17, 23s–30s.PubMedCrossRefGoogle Scholar
  44. 44.
    Liu, L., Shi, X., Bharadwaj, K. G., et al. (2009). DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. Journal of Biological Chemistry, 284, 36312–36323.PubMedCrossRefGoogle Scholar
  45. 45.
    Hernández-Corbacho, M. J., Jenkins, R. W., Clarke, C. J., Hannun, Y. A., Obeid, L. M., Snider, A. J., et al. (2011). Accumulation of long-chain glycosphingolipids during aging is prevented by caloric restriction. PLoS One, 6, e20411.PubMedCrossRefGoogle Scholar
  46. 46.
    Wu, M. Z., Katta, A., Gadde, M. K., et al. (2009). Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention. Plos One, 4(7), e6430.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Majd AlGhatrif
    • 1
    • 2
  • Vabren L. Watts
    • 1
  • Xiaolin Niu
    • 1
    • 3
  • Marc Halushka
    • 5
  • Karen L. Miller
    • 1
  • Konrad Vandegaer
    • 1
  • Djahida Bedja
    • 4
  • Karen Fox-Talbot
    • 5
  • Alicja Bielawska
    • 6
  • Kathleen L. Gabrielson
    • 4
  • Lili A. Barouch
    • 1
  1. 1.Division of Cardiology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Division of Hospital Medicine, Bayview Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of Cardiology, Tangdu HospitalThe Fourth Military Medical UniversityXi’anPeople’s Republic of China
  4. 4.Department of Comparative MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  5. 5.Department of PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  6. 6.Department of Biochemistry and Molecular BiologyMedical University of South CarolinaCharlestonUSA

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