Collectively, our data show that high-fat diet-induced obesity resulted in impaired cardiomyocyte function, upregulated Foxo3a transcription factor and mitochondrial damage without overt lipotoxicity or apoptosis.

The level of the obese gene product leptin is often positively correlated with body weight, supporting the notion that hyperleptinemia contributes to obesityassociated cardiac dysfunction. However, a link between leptin levels and cardiac function has not been elucidated. This study was designed to examine the role of leptin deficiency (resulting from a point mutation of the leptin gene) in cardiomyocyte contractile function. Mechanical properties and intracellular Ca 2+ transients were evaluated in ventricular myocytes from lean control and leptin-deficient ob/ob obese mice at 12 weeks of age. Cardiac ultrastructure was evaluated using transmission electron microscopy. ob/ob mice were overtly obese, hyperinsulinemic, hypertriglycemic, hypoleptinemic and euglycemic. Ultrastructural examination revealed swelling and disorganization of cristae in mitochondria from ob/ob mouse ventricular tissues. Cardiomyocytes from ob/ob mice displayed reduced expression of the leptin receptor Ob-R, larger cross-sectional area, decreased peak shortening and maximal velocity of shortening/relengthening, and prolonged relengthening but not shortening duration compared with lean counterparts. Consistent with mechanical characteristics, myocytes from ob/ob mice displayed reduced intracellular Ca 2+ release upon electrical stimulus associated with a slowed intracellular Ca 2+ decay rate. Interestingly, the contractile aberrations seen in ob/ob myocytes were significantly improved by in vitro leptin incubation. Contractile dysfunction was not seen in age-and gender-matched high fat-induced obese mice. These results suggested that leptin deficiency contributes to cardiac contractile dysfunction characterized by both systolic and diastolic dysfunction, impaired intracellular Ca 2+ hemostasis and ultrastructural derangement in ventricular myocytes.

Levels of the obese gene product leptin are often elevated in obesity and may contribute to obesity-induced cardiovascular complications. However, the role of leptin in obesity-associated cardiac abnormalities has not been clearly defined. This study was designed to determine the influence of high-fat diet-induced obesity on cardiac contractile response of leptin. Mechanical and intracellular Ca 2+ properties were evaluated using an IonOptix system in cardiomyocytes from adult rats fed low-and high-fat diets for 12 weeks. Cardiomyocyte contractile and intracellular Ca 2+ properties were examined including peak shortening, duration and maximal velocity of shortening/relengthening (TPS/TR 90 , ±dl/dt), Fura-2-fluorescence intensity change (ΔFFI), and intracellular Ca 2+ decay rate (τ). Expression of the leptin receptor (Ob-R) was evaluated by western blot analysis. High-fat diet increased systolic blood pressure and plasma leptin levels. PS and ±dl/dt were depressed whereas TPS and TR 90 were prolonged after high-fat diet feeding. Leptin elicited a concentration-dependent (0-1,000 nmol/l) inhibition of PS, ±dl/dt, and ΔFFI in low-fat but not high-fat diet-fed rat cardiomyocytes without affecting TPS and TR 90 . The Janus kinase 2 (JAK2) inhibitor AG490, the mitogenactivated protein kinase (MAPK) inhibitor SB203580, and the nitric oxide synthase (NOS) inhibitor L-NAME abrogated leptin-induced cardiomyocyte contractile response in low-fat diet group without affecting the high-fat diet group. High-fat diet significantly downregulated cardiac expression of Ob-R. Elevation of extracellular Ca 2+ concentration nullified obesity-induced cardiomyocyte mechanical dysfunction and leptin-induced depression in PS. These data indicate presence of cardiac leptin resistance in diet-induced obesity possibly associated with impaired leptin receptor signaling.

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Objective: High‐fat and marginally copper‐deficient diets impair heart function, leading to cardiac hypertrophy, increased lipid droplet volume, and compromised contractile function, resembling lipotoxic cardiac dysfunction. However, the combined effect of the two on cardiac function is unknown. This study was designed to examine the interaction between high‐fat and marginally copper‐deficient diets on cardiomyocyte contractile function. Research Methods and Procedures: Weanling male rats were fed diets incorporating a low‐ or high‐fat diet (10% or 45% of kcal from fat, respectively) with adequate (6 mg/kg) or marginally deficient (1.5 mg/kg) copper content for 12 weeks. Contractile function was determined with an IonOptix system including peak shortening (PS), time‐to‐PS, time‐to‐90% relengthening, maximal velocity of shortening/relengthening, and intracellular Ca2+ ([Ca2+]I) rise and decay. Results: Neither dietary treatment affected blood pressure or glucose levels, although the high‐fat diet elicited obesity and glucose intolerance. Both diets depressed PS, maximal velocity of shortening/relengthening, and intracellular Ca2+ ([Ca2+]I) rise and prolonged time‐to‐90% relengthening and Ca2+ decay without an additive effect between the two. Ca2+ sensitivity, apoptosis, lipid peroxidation, nitrosative damage, tissue ceramide, and triglyceride levels were unaffected by either diet or in combination. Phospholamban (PLB) but not sarco(endo)plasmic reticulum Ca2+‐ATPase was increased by both diets. Endothelial NO synthase was depressed with concurrent treatments. The electron transport chain was unaffected, although mitochondrial aconitase activity was inhibited by the high‐fat diet. Discussion: These data suggest that high‐fat and marginally copper deficient diets impaired cardiomyocyte contractile function and [Ca2+]i homeostasis, possibly through a similar mechanism, without obvious lipotoxicity, nitrosative damage, and apoptosis.