Cerebral FGF21-resistance as cause of the obesity-associated neurodegeneration

大脑 FGF21 抵抗是肥胖相关神经变性的原因

• 批准号: 257691728
• 负责人: Dr. Deborah Janowitz
• 金额: --
• 依托单位: Institut für Experimentelle Chirurgie mit Zentraler Versuchstierhaltung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/257691728?language=en
• 关键词: Cerebral; FGF21; resistance; cause; obesity

Metabolic syndrome, which includes visceral obesity, elevated triglycerides, elevated fasting blood sugar, high blood pressure and a decrease in HDL-cholesterol levels, comprises the most common chronic physical illness in modern society. Hypercholesterolemia may exert a negative effect on cognitive performance. One hormone, which regulates carbohydrate and lipid homeostasis and therefore the body weight, is the Fibroblast Growth Factor 21 (FGF21). Exogenous FGF21 reduces in obese patients the plasma concentration of triglycerides and cholesterol. However, it is also known that obese patients reveal a significant rise of hepatic and systemic FGF21 concentrations. This paradox is interpreted with a FGF21-resistance similar to an insulin- or leptin-resistance because obese patients show due to the low-grade inflammation a reduction of the FGF21 co-receptor, ß-klotho, in adipose tissue. If such a FGF21 resistance -mediated by a reduced ß-klotho expression- is also present in brain tissue should be clarified by using diet-induced obesity mice (DIO mice). It should be further investigated in a translational approach (DIO mice and obese patients) if there is a causality between reduced FGF21-responsiveness and neurodegenerative processes. This hypothesis is supported by the fact, that FGF21 activates the expression of the glucose transporter-1 (GLUT-1). Moreover, dementia is characterized by a low GLUT-1 expression. Thus, neuro-inflammation based on inflammatory processes in adipose tissue might be causative for the development of cerebral FGF21-resistance and therefore of the obesity-associated neurodegeneration. Further on, it should be analyzed if the obesity-associated neuro-inflammation and the accompanying FGF21-resistance can be reduced by dietary changes, by physical activity or by pharmaceutical approaches, and if this leads to a better cognitive performance. In summary, this project presents a possibility to combine and further to correlate findings of DIO mice and obese patients. Finally, the results on the FGF21-ß-klotho-GLUT-1 pathway, which are found in ex vivo and in in vivo analyses in the DIO mice, allow to shed light on the mechanisms underlying the FGF21-resistance in obese patients.

代谢综合征包括内脏肥胖、甘油三酯升高、空腹血糖升高、高血压和高密度脂蛋白-胆固醇水平下降，是现代社会最常见的慢性身体疾病。高胆固醇血症可能会对认知表现产生负面影响。其中一种激素是成纤维细胞生长因子21(FGF21)，它调节碳水化合物和脂肪的动态平衡，从而调节体重。外源性FGF21可降低肥胖患者的血浆甘油三酯和胆固醇浓度。然而，我们也知道肥胖患者肝脏和全身的FGF21浓度显著升高。这一悖论被解释为FGF21抵抗，类似于胰岛素或瘦素抵抗，因为肥胖症患者由于轻度炎症表现出脂肪组织中FGF21联合受体的减少。如果在脑组织中也存在这样的FGF21抵抗--由降低的ç-klotho表达介导--应该通过使用饮食诱导肥胖小鼠(DIO小鼠)来阐明。如果FGF21反应性降低和神经退变过程之间存在因果关系，则应进一步采用翻译方法(DIO小鼠和肥胖患者)进行研究。FGF21激活葡萄糖转运蛋白-1(GLUT-1)的表达的事实支持了这一假说。此外，痴呆症的特征是低GLUT-1表达。因此，基于脂肪组织炎症过程的神经炎症可能是导致大脑FGF21抵抗的原因，从而导致肥胖相关的神经变性。进一步，应该分析肥胖相关的神经炎症和伴随的FGF21-抵抗力是否可以通过饮食改变、体力活动或药物方法来减少，以及这是否会导致更好的认知表现。总而言之，该项目提供了一种将DIO小鼠和肥胖患者的研究结果结合起来并进一步相互关联的可能性。最后，在DIO小鼠体内和体外分析中发现的FGF21-？klotho-GLUT-1通路的结果，有助于阐明肥胖患者对FGF21耐药的机制。