Increased CD36 expression in middle-aged mice contributes to obesity-related cardiac hypertrophy in the absence of cardiac dysfunction

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 89; no. 5; pp. 459 - 469
• Main Authors: Sung, Miranda M. Y., Koonen, Debby P. Y., Soltys, Carrie-Lynn M., Jacobs, René L., Febbraio, Maria, Dyck, Jason R. B.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.05.2011; Springer Nature B.V
• Subjects: Aging - physiology; AMP-Activated Protein Kinases - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Cardiomegaly - etiology; Cardiomegaly - metabolism; Cardiomyopathies - metabolism; CD36 Antigens - genetics; CD36 Antigens - metabolism; Dietary Fats - adverse effects; Human Genetics; Immunoblotting; Internal Medicine; Male; Mice; Molecular Medicine; Obesity - metabolism; Obesity - physiopathology; Original Article; Cardiac hypertrophy; Aging; Signal transduction; Molecular biology
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-010-0720-4

As aging is a significant risk factor for the development of left ventricular hypertrophy and cardiovascular disease, we hypothesized that hearts from middle-aged mice may be more sensitive to the effects of a high fat (HF) diet than hearts from young mice. To investigate this, young (10–12 week old) and middle-aged (40–44 week old) male mice were fed a low fat (LF) or HF diet (10 or 60 kcal% fat, respectively) for 12 weeks. Following this 12-week period, we show that CD36 protein expression was not changed in hearts from young mice yet was increased 1.5-fold in the middle-aged HF group compared with LF-fed age-matched counterparts. Correlated with increased CD36 expression, middle-aged mice displayed a greater degree of cardiac hypertrophy compared with young mice when fed a HF diet, and this was observed in the absence of cardiac dysfunction. Furthermore, middle-aged CD36 knockout mice were protected against HF diet-induced cardiac hypertrophy, supporting a link between CD36 and cardiac hypertrophy. To further explore potential mechanisms that may explain why middle-aged mice are more susceptible to HF diet-induced cardiac hypertrophy, we investigated mediators of cardiac growth. We show that myocardial ceramide levels were significantly increased in middle-aged mice fed a HF diet compared with LF-fed controls, which was also correlated with inhibition of AMP-activated protein kinase (AMPK). Consistent with AMPK being a negative regulator of cardiac hypertrophy, decreased AMPK activity also resulted in the activation of the mTOR/p70S6K pathway, which is known to enhance protein synthesis associated with cardiac hypertrophy. Together, these data suggest that increased myocardial CD36 expression in hearts from middle-aged mice may contribute to HF diet-induced cardiac hypertrophy and that this may be mediated by elevated ceramide levels signaling through AMPK. Overall, we suggest that inhibition of CD36-mediated fatty acid uptake may prevent obesity-related cardiomyopathies in the middle-aged population.