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.

中枢抵抗肥胖信号瘦素和胰岛素会对全身能量平衡和葡萄糖代谢产生有害影响。我们和其他人已经综合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信号变化所介导的。随后，在下丘脑中参与调节瘦素和胰岛素信号转导的不同途径已经被确定；然而，它们之间的相互作用还知之甚少。我们发现了一条进化上高度保守的信号通路，WNT/GSK3通路是下丘脑中瘦素和胰岛素信号的一种新的和必要的整合因子。我们可以进一步证明，不是高瘦素血症本身似乎触发了对激素的中枢抵抗，而是高脂饮食引起的炎症导致了这种现象的表现。这项建议旨在描述下丘脑中瘦素和胰岛素相互作用的统一信号网络。我们将评估GSK3和重要的促炎因子，如JNK和IKKβ，在下丘脑的瘦素和胰岛素信号网络中的确切作用。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将恢复。描述这两种激素的复杂相互作用有可能显著提高我们对肥胖和相关严重疾病的发病机制的了解。

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.