University of Michigan, Department of Internal Medicine, Ann Arbor, MI, USA.
Atherosclerosis. 2011 Jan;214(1):81-5. doi: 10.1016/j.atherosclerosis.2010.10.009. Epub 2010 Oct 16.
Leptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. The primary aim of this study was to determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia.
Mice were generated with deficiency of apolipoprotein E (ApoE(-/-)) and either wild-type leptin receptor expression (Lepr(+/+), ApoE(-/-)), mutant leptin receptor expression defective in all leptin receptor signaling pathways (Lepr(db/db), ApoE(-/-)), or mutant leptin receptor expression with selective deficiency of leptin receptor-STAT3 signaling (Lepr(s/s), ApoE(-/-)). At 27 weeks of age (including 7 weeks on a Western diet), Lepr(db/db), ApoE(-/-) developed severe obesity, hypercholesterolemia, and increased atherosclerosis compared to Lepr(+/+), ApoE(-/-) mice. Despite similar obesity and hyperlipidemia to Lepr(db/db), ApoE(-/-) mice, Lepr(s/s), ApoE(-/-) developed less atherosclerosis than Lepr(db/db), ApoE(-/-) mice. Adipose tissue macrophage content, monocyte chemoattractant protein-1 and fatty-acid-binding protein 4 levels were also reduced in Lepr(s/s), ApoE(-/-) mice compared to Lepr(db/db), ApoE(-/-) mice.
In a mouse model of obesity and hyperlipidemia, leptin receptor-mediated STAT3-independent signaling pathways confer protection against atherosclerosis. These differences occur independently of leptin effects on energy balance.
瘦素是一种脂肪细胞衍生的激素，在临床前研究中已显示出有益的代谢作用和潜在的不良血管作用。本研究的主要目的是确定瘦素受体信号通路在肥胖和高脂血症背景下对动脉粥样硬化的影响。
生成载脂蛋白 E（ApoE(-/-)）缺乏和野生型瘦素受体表达（Lepr(+/+), ApoE(-/-)）、所有瘦素受体信号通路缺陷的突变瘦素受体表达（Lepr(db/db), ApoE(-/-)）或突变瘦素受体表达，其瘦素受体-STAT3 信号选择性缺乏（Lepr(s/s), ApoE(-/-)）的小鼠。在 27 周龄（包括 7 周的西方饮食）时，与 Lepr(+/+), ApoE(-/-) 小鼠相比，Lepr(db/db), ApoE(-/-) 发展为严重肥胖、高胆固醇血症和增加的动脉粥样硬化。尽管与 Lepr(db/db), ApoE(-/-) 小鼠具有相似的肥胖和高脂血症，Lepr(s/s), ApoE(-/-) 小鼠的动脉粥样硬化程度低于 Lepr(db/db), ApoE(-/-) 小鼠。与 Lepr(db/db), ApoE(-/-) 小鼠相比，Lepr(s/s), ApoE(-/-) 小鼠的脂肪组织巨噬细胞含量、单核细胞趋化蛋白-1 和脂肪酸结合蛋白 4 水平也降低。
在肥胖和高脂血症的小鼠模型中，瘦素受体介导的 STAT3 非依赖性信号通路对动脉粥样硬化具有保护作用。这些差异独立于瘦素对能量平衡的影响。
