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

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HDL-胆固醇水平降低，是现代社会最常见的慢性身体疾病。高胆固醇血症可能对认知能力产生负面影响。一种调节碳水化合物和脂质体内平衡并因此调节体重的激素是成纤维细胞生长因子21（FGF 21）。外源性FGF 21降低肥胖患者的甘油三酯和胆固醇的血浆浓度。然而，还已知肥胖患者显示肝脏和全身FGF 21浓度显著升高。这种矛盾被解释为FGF 21抗性类似于胰岛素抗性或瘦素抗性，因为肥胖患者由于低度炎症而显示脂肪组织中FGF 21共受体β-klotho的减少。如果这样的FGF 21抗性-由减少的β-klotho表达介导-也存在于脑组织中，应该通过使用饮食诱导的肥胖小鼠（DIO小鼠）来澄清。如果FGF 21反应性降低和神经退行性过程之间存在因果关系，则应在翻译方法（DIO小鼠和肥胖患者）中进一步研究。这一假设得到以下事实的支持：FGF 21激活葡萄糖转运蛋白-1（GLUT-1）的表达。此外，痴呆的特征在于低GLUT-1表达。因此，基于脂肪组织中的炎症过程的神经炎症可能是脑FGF 21抗性的发展以及因此肥胖相关的神经变性的原因。此外，还应该分析肥胖相关的神经炎症和伴随的FGF 21抗性是否可以通过饮食改变，身体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。总之，该项目提出了联合收割机的可能性，并进一步将DIO小鼠和肥胖患者的发现相关联。最后，在DIO小鼠中的离体和体内分析中发现的关于FGF 21-β-klotho-GLUT-1途径的结果允许阐明肥胖患者中FGF 21抗性的潜在机制。

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.