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.

对肥胖信号瘦素和胰岛素的中枢性抵抗对全身能量稳态和葡萄糖代谢有有害影响。我们和其他人已经全面表征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信号事件的改变介导的。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被确定；然而，人们对它们的相互作用知之甚少。我们发现了一个进化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传导的一个新的和必要的整合器。我们可以进一步证明，并不是高瘦素血症本身引发了对激素的中枢抵抗，而是由高脂肪喂养引起的炎症促成了这一现象的表现。这一建议旨在表征一个统一的信号网络瘦素和胰岛素相互作用在下丘脑。GSK3和主要的促炎激酶如JNK和ikkβ在下丘脑瘦素和胰岛素信号网络中的确切作用将被评估。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被恢复。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发病机制和相关严重疾病的认识。

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.