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CD40 Deficiency in Mice Exacerbates Obesity-induced Adipose Tissue Inflammation, Hepatic Steatosis and Insulin Resistance

机译:小鼠CD40缺乏加剧了肥胖诱导的脂肪组织炎症,肝脂肪变性和胰岛素抵抗

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摘要

The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation in adipose tissue and liver. The CD40 receptor and its ligand, CD40L, initiate immune cell signaling promoting inflammation, but conflicting data on CD40L null mice confound its role in obesity-associated insulin resistance. Here we demonstrate that CD40 receptor deficient mice on a high fat diet display the expected decrease in hepatic cytokine levels, but paradoxically exhibit liver steatosis, insulin resistance and glucose intolerance compared to their age-matched wild type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40 null mice compared to wild type mice. In contrast to liver, adipose tissue in CD40 deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8+ effector T-cells. In addition, ex vivo explants of epididymal adipose tissue from CD40(-/-) mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that, 1) CD40 null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate its inflammation in obesity, thereby protecting against hepatic steatosis.
机译:啮齿动物和人类中肥胖和2型糖尿病的病理生理学特征是脂肪组织和肝脏的低度炎症。 CD40受体及其配体CD40L启动免疫细胞信号传导,促进炎症反应,但CD40L空小鼠的数据矛盾,混淆了其在肥胖相关胰岛素抵抗中的作用。在这里,我们证明高脂饮食上的CD40受体缺陷型小鼠表现出预期的肝细胞因子水平降低,但与年龄相匹配的野生型对照相比,却表现出肝脂肪变性,胰岛素抵抗和葡萄糖耐量异常。高胰岛素-正常血糖钳夹研究还表明,与野生型小鼠相比,CD40无效小鼠在葡萄糖利用中的胰岛素抵抗。与肝脏相反,CD40缺乏动物的脂肪组织具有升高的细胞因子水平和炎性细胞(尤其是巨噬细胞和CD8 +效应T细胞)的浸润。此外,来自CD40(-/-)小鼠的附睾脂肪组织的离体外植体显示升高的基础和异丙肾上腺素刺激的脂解作用,表明脂质从内脏脂肪向肝脏的外排可能增加。这些发现表明,1)CD40无效的小鼠代表了具有减少的肝炎症的异常肝脂肪变性模型,以及2)CD40在脂肪组织中出乎意料地发挥了作用,从而减轻了肥胖症中的炎症,从而防止了肝脂肪变性。

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