Neuroendokrine Regulation der Energie und Glukosehomöostase- Vom zentralen WNT- Signalweg über hypothalamische Inflammation und Leptinsensitivität -

Obesity is one of the most common medical problems of the 21st century and represents a critical risk factor for the development of type II diabetes. Both metabolic derangements are associated with profound alterations of the neuroendocrine system, such as leptin resistance, which might present a possible link between these two diseases. In the last decade, the hypothalamus has been identified as a main insulin target tissue for the regulation of energy- and glucose- metabolism. Therefore, modifications of signalling pathways in the central nervous system are thought to be responsible for these metabolic disorders. In this thesis, we have shown that functional leptin- signalling of obese individuals is crucial for the maintenance of whole body glucose homeostasis. In neurons of the mediobasal hypothalamus (MBH), leptin inhibited the key enzyme of the WNT/β catenin- (WNT) pathway, glycogen-synthase-kinase 3β (GSK-3β), thereby activating this pathway. Furthermore, the glucose lowering capacity of leptin largely depends on neuronal WNT signalling. Moreover, acute inhibition of the central GSK-3β improved glucose tolerance and deceased food intake in leptin deficient mice. These results involved beneficial effect on central insulin- signalling and thereby decreasing hepatic glucose output. In contrast, increased hypothalamic GSK-3β activity was associated with obesity, increased food intake, disrupted whole body energy and glucose homeostasis and might be a result of reduced hypothalamic leptin sensitivity. Conclusively, these data suggest that the catabolic actions of central leptin- signalling are mediated via the WNT- pathway and that hypothalamic GSK-3β might be a key enzyme in the regulation of whole body glucose homeostasis. Besides the essential role of central leptin- signalling, we also detected other important aspects in the regulation of whole body glucose homeostasis, involving body fat mass. Recently, it was suggested that an enhanced release of cytokines by white adipose tissue might also activate hypothalamic pro-inflammatory pathways, thereby disrupting central insulin-signalling. Here, we observed increased activity of c-Jun N-terminale Kinase (JNK) in different nuclei of the MBH during obesity. Acute inhibition of this central kinase improved hypothalamic insulin- signalling and glucose tolerance in mice. Moreover, our data suggest that the observed effects were mediated via inhibition of central GSK-3β, further emphasizing a major role of this central kinase in the regulation of glucose metabolism. In addition to central JNK- signalling, pro-inflammatory signalling via central NF-κB is also associated with obesity and activation correlates with increased GSK-3β activity. Acute inhibition of central NF-κB- signalling, using the flavonoid Butein, strikingly improved glucose tolerance of obese and diabetic mice. Furthermore, long-term inhibition of NF-κB- signalling in the MBH, using a viral construct, decelerated diet induced obesity and improved whole-body glucose metabolism in mice fed a high fat diet. Moreover, this treatment increased oxygen consumption, energy expenditure and resting metabolic rate, which was associated with restored leptin sensitivity. Taken together, this thesis provides novel insights into the central regulation of whole body energy- and glucose metabolism. Our data indicate that the hypothalamic GSK-3β represents a key enzyme that mediates the metabolic actions of central leptin- and insulin- signalling. Pro-inflammatory pathways activate this central kinase, thereby inducing hypothalamic leptin resistance and subsequently disrupt the central regulation of whole body glucose homeostasis. Thus, this thesis reveals new potential therapeutic intervention in obesity and the development of type II diabetes.