The Function and Regulation of Tanycyte-Derived Hypothalamic Neurogenesis

 描述（由申请人提供）：肥胖是发展II型糖尿病（T2 D）的主要风险因素，这是一个主要且日益严重的公共卫生问题。肥胖症导致中枢瘦素和胰岛素抵抗，这反过来又会触发体内稳态神经回路的变化， 下丘脑这可能最终导致代谢综合征和T2 D的发展。成年下丘脑实质中的神经发生被高脂饮食（HFD）和瘦素缺乏破坏，导致促氧化性POMC表达神经元的数量减少。我们最近发现下丘脑伸长细胞作为第二个来源的新生神经元在成人下丘脑。我们的初步数据表明，虽然HFD和瘦素缺乏刺激伸长细胞衍生的神经发生，伸长细胞衍生的神经元促进野生型动物的体重增加，但抑制瘦素缺乏小鼠的体重增加。本文提出的研究旨在提高我们对伸长细胞衍生的神经元如何调节体重的理解，并确定饮食信号如何调节伸长细胞衍生的神经发生。首先，使用遗传学方法，我们计划调查的生理后果选择性地破坏和增强tanycyte-derived神经发生。其次，我们计划研究HFD诱导的细胞因子如CNTF和瘦素调节伸长细胞源性神经发生的分子机制。最后，我们建议确定的确切身份的tanycyte-derived神经元，并确定其突触后的目标。我们预计，这些研究将最终有助于设计治疗肥胖和T2 D的新疗法。

 DESCRIPTION (provided by applicant): Obesity is the main risk factor for developing type II diabetes (T2D), a major and growing public health problem. Elevated adiposity leads to central leptin and insulin resistance, which in turn can trigger changes in homeostatic neural circuitry in the hypothalamus. This can ultimately lead to the development of metabolic syndrome and T2D. Neurogenesis in the adult hypothalamic parenchyma is disrupted by high fat diet (HFD) and leptin deficiency, leading to a reduction in the number of anorexigenic POMC- expressing neurons. We have recently identified hypothalamic tanycytes as a second source of newborn neurons in adult hypothalamus. Our preliminary data suggests that while HFD and leptin deficiency stimulate tanycyte-derived neurogenesis, tanycyte-derived neurons promote weight gain in wildtype animals but inhibit weight gain in leptin-deficient mice. The studies proposed here aim to improve our understanding of how tanycyte-derived neurons regulate body weight, and to determine how dietary signals regulate tanycyte-derived neurogenesis. First, using genetic approaches, we plan to investigate the physiological consequences of selectively disrupting and enhancing tanycyte-derived neurogenesis. Second, we plan to investigate the molecular mechanisms by which both HFD-induced cytokines such as CNTF and leptin regulate tanycyte-derived neurogenesis. Finally, we propose to determine the exact identity of tanycyte-derived neurons and to identify their post-synaptic targets. We anticipate that these studies will ultimately assist in the design of novel therapies for treatment of obesity and T2D.