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。高胆固醇血症可能对认知能力产生负面影响。一种调节碳水化合物和脂质平衡从而调节体重的激素是成纤维细胞生长因子21 （FGF21）。外源性FGF21降低肥胖患者血浆中甘油三酯和胆固醇的浓度。然而，我们也知道肥胖患者肝脏和全身FGF21浓度显著升高。这个悖论可以用FGF21抵抗来解释，类似于胰岛素或瘦素抵抗，因为肥胖患者由于低度炎症表现出脂肪组织中FGF21共受体ß-klotho的减少。如果这种由减少的ß-klotho表达介导的FGF21抗性也存在于脑组织中，应该通过使用饮食诱导的肥胖小鼠（DIO小鼠）来澄清。如果fgf21反应性降低与神经退行性过程之间存在因果关系，应该在转化方法（DIO小鼠和肥胖患者）中进一步研究。这一假设得到了FGF21激活葡萄糖转运蛋白1 （GLUT-1）表达这一事实的支持。此外，痴呆症的特点是GLUT-1的低表达。因此，基于脂肪组织炎症过程的神经炎症可能导致大脑fgf21抵抗的发展，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抗性是否可以通过饮食改变、体育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，该项目提供了将DIO小鼠和肥胖患者的发现结合并进一步关联的可能性。最后，在DIO小鼠的体内和离体分析中发现的FGF21-ß- kloho - glut -1通路的结果，揭示了肥胖患者FGF21耐药的机制。

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.