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Title: HIGH-FAT DIET-INDUCED JUVENILE OBESITY LEADS TO CARDIOMYOCYTE DYSFUNCTION AND UPREGULATION OF FOXO3A TRANSCRIPTION FACTOR INDEPENDENT OF LIPOTOXICITY AND APOPTOSIS

Author
item RELLING, DAVID - UNIV OF NORTH DAKOTA
item ESBERG, LUCY - UNIV OF NORTH DAKOTA
item Johnson, William
item MURPHY, ERIC - UNIV OF NORTH DAKOTA
item CARLSON, EDWARD - UNIV OF NORTH DAKOTA
item Saari, Jack
item REN, JUN - UNIV OF NORTH DAKOTA

Submitted to: Journal of Hypertension
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/10/2005
Publication Date: 2/1/2006
Citation: Relling, D.P., Esberg, L.B., Fang, C.X., Johnson, W.T., Murphy, E.J., Carlson, E.C., Saari, J.T., Ren, J. 2006. High-fat diet-induced juvenile obesity leads to cardiomyocyte dysfunction and upregulation of Foxo3a transcription factor independent of lipotoxicity and apoptosis. Journal of Hypertension. 24:549-561.

Interpretive Summary: Obesity represents an alteration of fat metabolism that is often associated with diseases such as hypertension or diabetes, thus its effects on cardiovascular function are difficult to distinguish from those caused by other disease conditions. In the present study rats were fed a high fat diet that caused elevation of body weight without evidence of hypertension, diabetes or toxic events such as oxidative stress or change in lipid profiles. The obese rats nonetheless showed depression of heart function, illustrating that consumption of a high fat diet can affect the heart prior to the onset of diseases usually accompanying obesity.

Technical Abstract: Obesity is associated with dyslipidemia leading to elevated cardiac triglycerides and ceramide levels, apoptosis and compromised cardiac function. However, concomitant comorbidities such as hypertension and diabetes may bias the direct effect of obesity on cardiac function. Methods and Results: To determine the role of high-fat diet-induced obesity on cardiac excitation-contraction coupling, weanling male Sprague Dawley rats were fed diets incorporating 10% of kcal or 45% kcal from fat. Mechanical function of ventricular myocytes were evaluated including peak shortening (PS), time-to-PS (TPS), time-to 90% relengthening (TR**90) and maximal velocity of shortening and relengthening (± dL/dt). Intracellular Ca**2+ properties were assessed using Fura-2 fluorescent microscopy. High-fat diet-induced obesity depressed PS, ± dL/dt, prolonged TPS and TR**90, reduced intracellular CA**2+ release and clearing rate in the absence of hypertension, diabetes or characteristics of lipotoxicity. Myocyte response to high stimulus frequency but not extracellular CA**2+ was compromised. SERCA2a and phospholamban levels were increased although the ratio of the two was unchanged in high-fat diet group. Oxidative injury and apoptosis were similar between the high and low diet groups. Levels of eNOS, iNOS, triglycerides, and ceramide were also similar between the groups. Conclusions: The high-fat diet-induced obesity resulted in impaired cardiac mechanical function in ventricular myocytes without overt oxidative damage, lipotoxicity or apoptosis. These data suggest that high-fat diet-induced obesity in young rats depresses contractile function of cardiac myocytes prior to the onset of diabetes, hypertension and lipotoxicity.