Disruption of endothelial Pfkfb3 ameliorates diet-induced murine insulin resistance.
Disruption of endothelial Pfkfb3 ameliorates diet-induced murine insulin resistance.
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DOI：
10.1530/joe-20-0524
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发表时间：
2021-06
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通讯作者：
Qiuhua Yang;Jiean Xu;Qian Ma;Zhiping Liu;Yaqi Zhou;Yongfeng Cai;Xiaoxiao Mao;D. Stepp;Neal Weintraub;D. Fulton;Mei Hong;Yuqing Huo
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作者：
Qiuhua Yang;Jiean Xu;Qian Ma;Zhiping Liu;Yaqi Zhou;Yongfeng Cai;Xiaoxiao Mao;D. Stepp;Neal Weintraub;D. Fulton;Mei Hong;Yuqing Huo
过度营养诱导的内皮炎症在高脂饮食（HFD）诱导的动物胰岛素抵抗中起着至关重要的作用。内皮糖酵解在内皮炎症和增殖中起关键作用，但其在饮食诱导的内皮炎症和随后的胰岛素抵抗中的作用尚未阐明。PFKFB 3是一种关键的糖酵解调节因子，在体内喂食HFD的C57 BL/6 J小鼠的脂肪血管内皮细胞和体外棕榈酸酯（PA）处理的原代人脂肪微血管内皮细胞（HAMEC）中观察到其表达增加。我们产生了对内皮细胞具有选择性的Pfkfb 3缺陷的小鼠，以检查内皮Pfkfb 3在代谢器官中的内皮炎症和HFD诱导的胰岛素抵抗的发展中的作用。EC Pfkfb 3缺陷型小鼠表现出减轻HFD诱导的胰岛素抵抗，包括体重和脂肪量降低，葡萄糖清除率和胰岛素敏感性改善，肥胖和肝脂肪变性减轻。机制上，培养的PFKFB 3敲除HAMEC显示PA诱导的NF-κB活化降低，从而抑制粘附分子表达和单核细胞粘附。总之，这些结果表明，增加内皮PFKFB 3表达促进饮食诱导的炎症反应和随后的胰岛素抵抗，表明内皮代谢改变在胰岛素抵抗的发展中起重要作用。
Overnutrition-induced endothelial inflammation plays a crucial role in high fat diet (HFD)-induced insulin resistance in animals. Endothelial glycolysis plays a critical role in endothelial inflammation and proliferation, but its role in diet-induced endothelial inflammation and subsequent insulin resistance has not been elucidated. PFKFB3 is a critical glycolytic regulator, and its increased expression has been observed in adipose vascular endothelium of C57BL/6J mice fed with HFD in vivo, and in palmitate (PA)-treated primary human adipose microvascular endothelial cells (HAMECs) in vitro. We generated mice with Pfkfb3 deficiency selective for endothelial cells to examine the effect of endothelial Pfkfb3 in endothelial inflammation in metabolic organs and in the development of HFD-induced insulin resistance. EC Pfkfb3-deficient mice exhibited mitigated HFD-induced insulin resistance, including decreased body weight and fat mass, improved glucose clearance and insulin sensitivity, and alleviated adiposity and hepatic steatosis. Mechanistically, cultured PFKFB3 knockdown HAMECs showed decreased NF-κB activation induced by PA, and consequent suppressed adhesion molecule expression and monocyte adhesion. Taken together, these results demonstrate that increased endothelial PFKFB3 expression promotes diet-induced inflammatory responses and subsequent insulin resistance, suggesting that endothelial metabolic alteration plays an important role in the development of insulin resistance.