Central nervous and metabolic effects of intranasal leptin in diet induced obesity and studies on leptin receptor signal transduction induced by leptin fragments

肥胖的主要特征之一是中枢神经系统对瘦素的抵抗力，瘦素是一种白色脂肪组织反馈激素。这种瘦素抵抗主要位于血脑屏障(BBB)，瘦素直接应用于脑内仍然有效。大脑也可以通过鼻腔(I.N.)进行非侵入性靶向治疗。瘦素的应用；通过嗅神经运输，从而绕过血脑屏障。最近，我们已经证明，在瘦大鼠中，I.N.瘦素有效地进入大脑，影响能量动态平衡。从I.N.开始。瘦素确实绕过了血脑屏障，预计它对肥胖也是有效的，为人类提供了一种可能的治疗方法。为了进一步阐明这一点，我们将研究I.N的影响。瘦素在饮食诱导的大鼠肥胖中，是最接近人类肥胖的动物实验模型。我们将研究这种给药模式的内分泌和代谢后遗症，并检测瘦素受体下游神经肽的大脑表达。天然瘦素分子的一些片段也有效地刺激了瘦素受体，因为它们的大小被认为更容易渗透到大脑中。然而，关于它们对能量平衡和瘦素受体信号转导的影响的数据很少。在体外模型中，我们将研究瘦素片段对信号转导的影响。总而言之，我们将检验我们的假设，即I.N.瘦素在肥胖中是有效的，我们将根据其在I.N中的潜在可行性来表征瘦素片段。肥胖的治疗。

One of the main features of obesity is a central nervous resistance to leptin, a white adipose tissue feedback hormone. This leptin resistance is mainly located at the blood brain barrier (BBB), leptin applied directly into the brain remains effective. The brain can also be targeted non-invasively by intranasal (i.n.) leptin application; transport is via the olfactory nerve, thus circumventing the BBB. Recently we have shown that in lean rats i.n. leptin effectively enters the brain to affect energy homeostasis. Since i.n. leptin does circumvent the BBB, it is expected to be effective in obesity as well, offering a possible therapeutic approach also in humans. To further elucidate this, we will study the effects of i.n. leptin in rats with diet induced obesity, the animal experimental model best resembling human obesity. We will study the endocrine and metabolic sequelae of this mode of administration and examine the brain expression of neuropeptides downstream of the leptin receptor. Some fragments of the native leptin molecule, which are supposed to penetrate more easily into the brain because of their size, are also effectively stimulating leptin receptors. However only very few data exist on their effects on energy homeostasis and on leptin receptor signal transduction. In an in-vitro model we will study signal transduction effects by leptin fragments. In summary, we will test our hypothesis that i.n. leptin is effective in obesity and we will characterise leptin fragments with respect to their potential feasibility in the i.n. treatment of obesity.