Hall Michael E, Maready Matthew W, Hall John E, Stec David E
Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi; and Department of Medicine/Division of Cardiology, University of Mississippi Medical Center, Jackson, Mississippi.
Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi; and.
Am J Physiol Endocrinol Metab. 2014 Aug 1;307(3):E316-25. doi: 10.1152/ajpendo.00005.2014. Epub 2014 Jun 17.
Increased leptin levels have been suggested to contribute to cardiac hypertrophy and attenuate cardiac lipid accumulation in obesity, although it has been difficult to separate leptin's direct effects from those caused by changes in body weight and adiposity. To determine whether leptin attenuates cardiac lipid accumulation in obesity or directly causes left ventricular hypertrophy (LVH), we generated a novel mouse model in which the long form of the leptin receptor (LepR) was "rescued" only in cardiomyocytes of obese db/db mice. Reexpression of cardiomyocyte leptin receptors in db/db mice did not cause LVH but reduced cardiac triglycerides and improved cardiac function. Compared with lean wild-type (WT) or db/db-cardiac LepR rescue mice, db/db mice exhibited significantly lower E/A ratio, a measurement of early to late diastolic filling, which averaged 1.5 ± 0.07 in db/db vs. 1.9 ± 0.08 and 1.8 ± 0.11 in WT and db/db-cardiac LepR rescue mice, respectively. No differences in systolic function were observed. Although db/db and db/db-cardiac LepR rescue mice exhibited similar increases in plasma triglycerides, insulin, glucose, and body weight, cardiac triglycerides were significantly higher in db/db compared with WT and db/db cardiac LepR rescue mice, averaging 13.4 ± 4.2 vs. 3.8 ± 1.6 vs. 3.8 ± 0.7 mg/g, respectively. These results demonstrate that despite significant obesity and increases in plasma glucose and triglycerides, db/db cardiac LepR rescue mice are protected against myocardial lipid accumulation. However, we found no evidence that leptin directly causes LVH.
尽管很难将瘦素的直接作用与体重和肥胖变化所引起的作用区分开来，但已有研究表明，肥胖状态下瘦素水平升高会导致心脏肥大，并减轻心脏脂质蓄积。为了确定瘦素是否能减轻肥胖状态下的心脏脂质蓄积或直接导致左心室肥厚（LVH），我们构建了一种新型小鼠模型，在肥胖的db/db小鼠的心肌细胞中仅“挽救”长型瘦素受体（LepR）。db/db小鼠心肌细胞瘦素受体的重新表达并未导致左心室肥厚，但降低了心脏甘油三酯水平并改善了心脏功能。与瘦的野生型（WT）或db/db-心脏LepR挽救小鼠相比，db/db小鼠的E/A比值显著更低，E/A比值是舒张早期至晚期充盈的一项测量指标，db/db小鼠的E/A比值平均为1.5±0.07，而WT小鼠和db/db-心脏LepR挽救小鼠分别为1.9±0.08和1.8±0.11。未观察到收缩功能的差异。尽管db/db小鼠和db/db-心脏LepR挽救小鼠的血浆甘油三酯、胰岛素、葡萄糖和体重均有相似程度的升高，但与WT小鼠和db/db-心脏LepR挽救小鼠相比，db/db小鼠的心脏甘油三酯水平显著更高，平均分别为13.4±4.2、3.8±1.6和3.8±0.7mg/g。这些结果表明，尽管存在显著肥胖以及血糖和甘油三酯升高的情况，但db/db-心脏LepR挽救小鼠可免受心肌脂质蓄积的影响。然而，我们没有发现瘦素直接导致左心室肥厚的证据。
