Department of Pediatrics; University of California, San Diego; San Diego, CA USA.
Adipocyte. 2013 Jul 1;2(3):170-5. doi: 10.4161/adip.24144. Epub 2013 Apr 19.
Obesity has reached epidemic proportions in most of the western world. With obesity comes a variety of adverse health effects such as insulin resistance, dyslipidemia, hypertension, glucose intolerance, and hepatic steatosis. It has become clear that a state of low grade chronic inflammation, typically associated with obesity, and characterized by macrophage infiltration of adipose tissue (AT) and increased production of pro-inflammatory cytokines, plays a crucial role in the development of insulin resistance. The pathogenic mechanisms resulting in AT macrophage recruitment are under intense investigation and remain incompletely understood. We recently demonstrated that lysosomal permeabilization, and subsequent Cathepsin B (CTSB) activation, occurs at the early stages of high fat diet induced weight gain and is preceded by macrophage infiltration into hypertrophied AT resulting in adipocyte cell death through mitochondrial dysfunction. In this report, we demonstrated that another key Cathepsin, Cathepsin D (CTSD), is also activated at the early stages of weight gain. In addition, activated CTSD induced proapoptotic protein activation. In conclusion, our data identify lysosomal CTSD as a potential key mediator of adipocyte cell death during weight gain and obesity.
肥胖在大多数西方国家已经达到流行程度。肥胖会带来各种不良的健康影响，如胰岛素抵抗、血脂异常、高血压、葡萄糖不耐受和肝脂肪变性。现在已经很清楚，一种低度慢性炎症状态，通常与肥胖有关，其特征是脂肪组织（AT）中巨噬细胞浸润和促炎细胞因子产生增加，在胰岛素抵抗的发展中起着至关重要的作用。导致 AT 巨噬细胞募集的发病机制正在深入研究，但仍不完全清楚。我们最近证明，溶酶体通透性，随后组织蛋白酶 B（CTSB）的激活，发生在高脂肪饮食诱导体重增加的早期阶段，并且之前是巨噬细胞浸润到肥大的 AT 中，导致脂肪细胞通过线粒体功能障碍死亡。在本报告中，我们证明了另一种关键的组织蛋白酶 D（CTSD）也在体重增加的早期阶段被激活。此外，激活的 CTSD 诱导了促凋亡蛋白的激活。总之，我们的数据表明溶酶体 CTSD 是体重增加和肥胖期间脂肪细胞死亡的潜在关键介质。
