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

• Applicants: Dr. Deborah Janowitz; Privatdozentin Dr. Angela Kuhla
• Subject Area: Gastroenterology ; Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 257691728

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.

• DFG Programme: Research Grants