Pinch 蛋白在肥胖发生过程中的作用和机制探究

哺乳动物粘附因子Pinch蛋白可以激活整合素，促进细胞-细胞外基质的粘附和迁移，但其在脂肪组织及全身代谢中的作用仍不清楚。本项研究中我们发现高脂饮食饲养显著增加小鼠白色脂肪组织中Pinch1和Pinch2的表达。此外，在ob/ob小鼠和肥胖病人的白色脂肪组织中，Pinch1的表达显著上升。由于脂肪细胞特异性缺失Pinch1或者全身敲除Pinch2的小鼠没有任何显著的表型，并且Pinch1与Pinch2在功能上有代偿，本课题利用全身敲除Pinch2并在脂肪细胞敲除Pinch1的小鼠模型研究Pinch在脂肪组织中的功能。我们发现敲除小鼠在高脂饮食条件下表现出显著的体重和白色脂肪组织重量减少，但是在正常饮食条件下没有变化。Pinch缺失改善高脂饮食诱导的小鼠的葡萄糖不耐受、胰岛素抵抗和脂肪肝，并且轻微但是显著性地增加小鼠的能量消耗。同时Pinch缺失减小脂肪细胞体积、改变脂肪细胞体积分布、促进性腺白色脂肪组织的细胞凋亡并轻微促进皮下白色脂肪组织的细胞凋亡。体外研究表明Pinch缺失通过激活Bim/Caspase-8途径促进细胞凋亡。在体内脂肪细胞特异性敲除Caspase-8可以逆转Pinch缺失对小鼠肥胖、葡萄糖不耐受、胰岛素抵抗和脂肪肝的保护作用。在此，我们证明Pinch通过调控脂肪细胞凋亡发挥调节脂肪组织重量、葡萄糖和脂质代谢的功能。我们的研究发现为代谢性疾病例如肥胖和糖尿病的预防和治疗提供了潜在靶点。

The mammalian focal adhesion proteins Pinch 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 and Pinch2 in white adipose tissue (WAT) in mice. Furthermore, expression of Pinch1 is largely upregulated in WAT in ob/ob mice and obese humans. While mice with loss of Pinch1 in adipocytes or global Pinch2 do not display any notable phenotypes and Pinch1 is compensatory in function with Pinch2, we use mice model with Pinch1 deletion in adipocytes and Pinch2 global knockout to study the function of Pinch1 in adipose tissue. Pinch deletion significantly decreases body weight and WAT mass in HFD-fed, but not normal chow diet–fed, mice. Pinch loss ameliorates HFD-induced glucose intolerance, insulin resistance 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, insulin resistance and fatty liver in mice. Thus, our findings demonstrate a key role of Pinch in control of adipose mass, glucose, and fat metabolism via modulation of adipocyte apoptosis. We may define a potential target for the prevention and treatment of metabolic diseases, such as obesity and diabetes.

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