Molecular mechanisms underlying cardiac dysfunction and subsequent heart failure in diabetic cardiomyopathy are incompletely understood. Initially we intended to test the role of GRK2, a potential mediator of cardiac dysfunction in diabetic cardiomyopathy, but found that control animals on HFD did not develop cardiomyopathy. Cardiac function was preserved in both wildtype and GRK2 knockout animals fed high fat diet as indicated by preserved left ventricular ejection fraction (LVEF) although heart mass was increased. The absence of cardiac dysfunction led us to rigorously evaluate the utility of diet-induced obesity to model diabetic cardiomyopathy in mice. Using pure C57BL/6J animals and various diets formulated with different sources of fat- lard (32% saturated fat, 68% unsaturated fat) or hydrogenated coconut oil (95% saturated fat), we consistently observed left ventricular hypertrophy, preserved LVEF and preserved contractility measured by invasive hemodynamics in animals fed high fat diet. Gene expression patterns that characterize pathological hypertrophy were not induced but a modest induction of various collagen isoforms and matrix metalloproteinases were observed in heart with high fat diet feeding. PPARa-target genes that enhance lipid utilization such as Pdk4, CD36, AcadL and Cpt1b were induced, but mitochondrial energetics were not impaired. These results suggest while long-term fat feeding in mice induces cardiac hypertrophy and increases cardiac fatty acid metabolism, it may not be sufficient to activate pathological hypertrophic mechanisms that impair cardiac function or induce cardiac fibrosis. Thus, additional factors that are currently not understood may contribute to the cardiac abnormalities previously reported by many groups.

中文翻译：

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C57BL/6J 小鼠心脏对膳食脂肪过载的功能恢复

糖尿病心肌病的心脏功能障碍和随后的心力衰竭的分子机制尚不完全清楚。最初我们打算测试 GRK2 的作用，GRK2 是糖尿病心肌病中心脏功能障碍的潜在介质，但发现使用 HFD 的对照动物没有发生心肌病。尽管心脏质量增加，但如保留的左心室射血分数 (LVEF) 所示，在喂食高脂肪饮食的野生型和 GRK2 基因敲除动物中，心脏功能均得以保留。没有心脏功能障碍使我们严格评估饮食诱导的肥胖在小鼠糖尿病心肌病模型中的效用。使用纯 C57BL/6J 动物和用不同来源的脂肪（32% 饱和脂肪，68% 不饱和脂肪）或氢化椰子油（95% 饱和脂肪）配制的各种饮食，我们一直观察到左心室肥厚，保留的 LVEF 和保留的收缩力，通过侵入性血流动力学测量高脂肪饮食的动物。没有诱导表征病理性肥大的基因表达模式，但在高脂肪饮食喂养的心脏中观察到各种胶原亚型和基质金属蛋白酶的适度诱导。增强脂质利用的 PPARa 靶基因如 Pdk4、CD36、AcadL 和 Cpt1b 被诱导，但线粒体能量学未受损。这些结果表明，虽然小鼠的长期脂肪喂养诱导心脏肥大并增加心脏脂肪酸代谢，但它可能不足以激活损害心脏功能或诱导心脏纤维化的病理性肥大机制。因此，