BACKGROUND The increasing risk of obesity and diabetes among other metabolic disorders are the consequence of shifts in dietary patterns with high caloric-content food intake. We previously reported that megalin regulates energy homeostasis using blood-brain barrier (BBB) endothelial megalin-deficient (EMD) mice, since these animals developed obesity and metabolic syndrome upon normal chow diet administration. Obesity in mid-life appears to be related to greater dementia risk and represents an increasing global health issue. We demonstrated that EMD phenotype induced impaired learning ability and recognition memory, neurodegeneration, neuroinflammation, reduced neurogenesis, and mitochondrial deregulation associated with higher mitochondrial mass in cortical tissues. METHODS EMD mice were subjected to normal chow and high-fat diet (HFD) for 14 weeks and metabolic changes were evaluated. RESULTS Surprisingly, BBB megalin deficiency protected against HFD-induced obesity improving glucose tolerance and preventing hepatic steatosis. Compared to wild type (wt), the brain cortex in EMD mice showed increased levels of the mitochondrial biogenesis regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2), a thermogenic protein involved in the regulation of energy metabolism. This agreed with the previously found increased mitochondrial mass in the transgenic mice. Upon HFD challenge, we demonstrated these two proteins were found elevated in wt mice but reported no changes over the already increased levels in EMD animals. CONCLUSION We propose a protective role for megalin on diet-induce obesity, suggesting this could be related to metabolic disturbances found in dementia through brain endocrine system communications.

中文翻译：

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脑中巨蛋白的内皮特异性缺乏可保护小鼠免受高脂饮食的挑战。

背景技术在其他代谢性疾病中，肥胖和糖尿病的风险增加是高热量食物摄入的饮食方式转变的结果。我们以前曾报道过，巨蛋白使用血脑屏障（BBB）内皮巨蛋白缺乏（EMD）小鼠来调节能量稳态，因为这些动物在正常饮食饮食下会产生肥胖和代谢综合症。中年肥胖似乎与痴呆症风险增加有关，并且代表着日益严重的全球健康问题。我们证明，EMD表型可导致学习能力和识别记忆受损，神经变性，神经炎症，神经发生减少以及与皮质组织中较高线粒体质量相关的线粒体失调。方法对EMD小鼠进行正常饮食和高脂饮食（HFD），持续14周，并评估其代谢变化。结果出乎意料的是，BBB巨蛋白缺乏症可预防HFD引起的肥胖症，从而改善葡萄糖耐量并预防肝脂肪变性。与野生型（wt）相比，EMD小鼠的大脑皮质显示线粒体生物发生调节剂，过氧化物酶体增殖物激活的受体γcoactivator-1α（PGC-1α）和解偶联蛋白2（UCP2）的水平升高。调节能量代谢。这与先前在转基因小鼠中发现的线粒体质量增加一致。在HFD攻击后，我们证明了这两种蛋白在wt小鼠中被发现升高，但与EMD动物中已经升高的水平相比没有变化。