Unravelling a unifying network for leptin and insulin interaction in the hypothalamus as a potential link between obesity and associated diseases. Genetherapeutic, pharmacological and nutritive interventions of crucial signalling pathways.

肥胖的中枢抵抗信号瘦素和胰岛素对全身能量平衡和糖代谢有有害影响。我们和其他人已经全面地描述了这种抵抗在很大程度上是由下丘脑神经元中瘦素和胰岛素受体远端的改变的信号事件介导的。随后，不同的途径参与介导瘦素和胰岛素信号转导下丘脑已被确定，但是，他们的相互作用只是知之甚少。我们确定了一个进化高度保守的信号通路，WNT/GSK 3通路作为一个新的和必不可少的整合瘦素和胰岛素信号在下丘脑。我们可以进一步证明，高瘦素血症本身似乎并不触发对激素的中枢抵抗，而是高脂肪喂养诱导的炎症促成了这种现象的表现。该建议旨在表征下丘脑中瘦素和胰岛素相互作用的统一信号网络。将评估GSK 3和显著的促炎性激酶如JNK和IKK β在下丘脑中的瘦素和胰岛素信号传导网络中的确切作用。使用最先进的基因治疗和药理学方法，下丘脑炎症将被逆转，受损的瘦素和胰岛素信号传导将被恢复。描绘这两种激素的复杂相互作用有可能显着提高我们对肥胖和相关严重疾病的发病机制的认识。

Central resistance to the adiposity signals leptin and insulin has deleterious effects on whole body energy homeostasis and glucose metabolism. It has been comprehensively characterized by us and others that this resistance is largely mediated by altered signalling events distal to the leptin and insulin receptors in neurons of the hypothalamus. Subsequently, different pathways involved in mediating leptin and insulin signal transduction in the hypothalamus have been identified; however, their interplay is only poorly understood. We identified an evolutionary highly conserved signalling pathway, the WNT/GSK3 pathway as a novel and essential integrator of both leptin and insulin signalling in the hypothalamus. We could furthermore demonstrate that not hyperleptinemia per se appears to trigger central resistance to the hormone rather inflammation induced by high fat feeding contributes to the manifestation of this phenomenon. This proposal aims at characterizing a unifying signalling network of leptin and insulin interaction in the hypothalamus. The exact role of GSK3 and prominent pro-inflammatory kinases such as JNK and IKKbeta in the network of leptin and insulin signalling in the hypothalamus will be assessed. Using state of the art genetherapeutic and pharmacological methodologies hypothalamic inflammation shall be reversed and impaired leptin and insulin signalling restored. Delineating the complex interaction of both hormones has the potential to significantly improve our knowledge about the pathogenesis of obesity and associated severe diseases.