Pinch Loss Ameliorates Obesity, Glucose Intolerance, and Fatty Liver by Modulating Adipocyte Apoptosis in Mice
Pinch Loss Ameliorates Obesity, Glucose Intolerance, and Fatty Liver by Modulating Adipocyte Apoptosis in Mice
复制标题
捏力损失通过调节小鼠脂肪细胞凋亡来改善肥胖、葡萄糖耐受不良和脂肪肝
DOI：
10.2337/db21-0392
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发表时间：
2021-11-01
期刊：
影响因子：
7.7
通讯作者：
Xiao, Guozhi
中科院分区：
文献类型：
--
作者：
Gao, Huanqing;Zhong, Yiming;Xiao, Guozhi
哺乳动物黏着斑蛋白Pinch 1/2激活整合素并促进细胞-细胞外基质粘附和迁移;然而，它们在脂肪组织和代谢中的作用尚不清楚。在这里，我们发现，高脂饮食（HFD）喂养显着增加Pinch 1/2蛋白在小鼠的白色脂肪组织（WAT）的表达。此外，Pinch 1的表达在瘦素缺乏的ob/ob 2型糖尿病小鼠和肥胖人类的WAT中大幅上调。虽然脂肪细胞中Pinch 1或整体Pinch 2缺失的小鼠未显示出任何显著的表型，但在HFD喂养但非正常饲料喂养的小鼠中，脂肪细胞中Pinch 1和Pinch 2整体缺失显著降低体重和WAT质量，但不降低棕色脂肪组织质量。捏损失改善HFD诱导的葡萄糖耐受不良和脂肪肝。在HFD挑战后，捏损轻微但显著地加速能量消耗。虽然捏损失减少脂肪细胞的大小和改变脂肪细胞的大小分布，它大大加速细胞凋亡，主要是在附睾WAT和皮下WAT在较小程度上。体外研究表明，Pinch损失通过激活Bim/Caspase-8途径加速脂肪细胞凋亡。在体内，脂肪细胞中Caspase-8表达的基因消除基本上消除了Pinch缺乏对小鼠肥胖、葡萄糖耐受不良和脂肪肝的改善作用。因此，我们证明了一个以前未知的功能，捏控制脂肪质量，葡萄糖和脂肪代谢，通过调制脂肪细胞凋亡。我们可能会定义一个新的目标，预防和治疗代谢性疾病，如肥胖症和糖尿病。
The mammalian focal adhesion proteins Pinch1/2 activate integrins and promote cell-extracellular matrix adhesion and migration; however, their roles in adipose tissue and metabolism are unclear. Here we find that high-fat diet (HFD) feeding dramatically increases expression of Pinch1/2 proteins in white adipose tissue (WAT) in mice. Furthermore, expression of Pinch1 is largely upregulated in WAT in leptin-deficient ob/ob type 2 diabetic mice and obese humans. While mice with loss of Pinch1 in adipocytes or global Pinch2 do not display any notable phenotypes, deleting Pinch1 in adipocytes and Pinch2 globally significantly decreases body weight and WAT mass, but not brown adipose tissue mass, in HFD-fed, but not normal chow diet-fed, mice. Pinch loss ameliorates HFD-induced glucose intolerance and fatty liver. After HFD challenge, Pinch loss slightly but significantly accelerates energy expenditure. While Pinch loss decreases adipocyte size and alters adipocyte size distribution, it greatly accelerates cell apoptosis primarily in epididymal WAT and to a lesser extent in subcutaneous WAT. In vitro studies demonstrate that Pinch loss accelerates adipocyte apoptosis by activating the Bim/Caspase-8 pathway. In vivo, genetic ablation of Caspase-8 expression in adipocytes essentially abolishes the ameliorating effects of Pinch deficiency on obesity, glucose intolerance, and fatty liver in mice. Thus, we demonstrate a previously unknown function of Pinch in control of adipose mass, glucose, and fat metabolism via modulation of adipocyte apoptosis. We may define a novel target for the prevention and treatment of metabolic diseases, such as obesity and diabetes.