Obesity and regulation of energy homeostasis in Drosophila melanogaster

描述(申请人提供)：肥胖是一种复杂的疾病，由控制能量消耗和支出平衡的特定生物途径的错误调节引起，并与从心脏病、糖尿病到几种癌症的一系列健康问题有关。相反，卡路里限制已被证明可以降低实验室小鼠的自发性肿瘤发生率。然而，很明显，肥胖不仅仅是食物摄入过多的结果。在确定与肥胖有关的途径方面取得了重大进展，但需要对这种疾病有更深入的了解，以满足对有效治疗日益增长的需求。肥胖研究领域需要一种实验系统，将基因操作的适应性与人类的一些生理复杂性结合起来。 这项拟议的研究将发展黑腹果蝇作为一个模型系统，以确定控制能量动态平衡的新途径。苍蝇提供了广泛的遗传工具和这些研究所需的生理复杂性，因为它们拥有感觉、循环和储存器官。 维持能量平衡需要神经系统的协调(感觉饱腹感和调节 行为)和储能组织(以脂肪/糖的形式储存能量或动员能量)。拟议的研究将确定改进的饮食对能量储存的类型和水平的影响，并确定组成能量稳态调节网络的途径，包括哪些器官感知和处理食物来源以及能量水平的生理变化。具体地说，这些实验的目的是：(1)确定饮食对摄入量(食物消耗的数量/类型)和使用(存储的能量数量/类型)之间的平衡的影响；(2)解决神经系统在调节总体生理能量平衡方面的作用，并确定涉及大脑的哪些特定区域；以及(3)确定负责维持机体能量平衡的器官间通信路径。发育中的果蝇将被喂以改良的饲料，并将评估对脂肪水平和其他形式的能量储存、食物消耗率以及整体生长和发育的影响。为了确定大脑中正常能量平衡所需的区域，将使用基因工程苍蝇来消除特定神经元组的功能，并确定对储存的脂肪和摄入的食物水平的影响。最后，将进行全基因组筛查，以确定影响脂肪储存和/或食物消耗率的基因。了解容易导致肥胖的饮食和生理条件将提高我们对这种疾病的理解，并确定其治疗和预防的潜在靶点。

DESCRIPTION (provided by applicant): Obesity is a complex disorder resulting from misregulation of specific biological pathways controlling the balance between energy consumption and expenditure, and is associated with health problems ranging from heart disease and diabetes to several kinds of cancer. Conversely, caloric restriction has been shown to result in a reduction of incidence of spontaneous tumors in laboratory mice. However, it is clear that obesity is not simply an effect of excessive food intake. Significant progress has been made towards identifying pathways involved in obesity, but a deeper understanding of the disease is required in order to meet the growing demand for effective treatments. The field of obesity research is in need of an experimental system that can combine amenability to genetic manipulation with some of the physiological complexity of humans. The proposed research will develop Drosophila melanogaster as a model system to identify new pathways controlling energy homeostasis. Flies offer extensive genetic tools and the physiological complexity required for these studies, as they possess sensory, circulatory and storage organs. Maintaining energy balance requires coordination of the nervous system (sensing satiety and regulating behavior) and energy storage tissues (storing energy as fat/sugar or mobilizing it). The proposed studies will determine the effects of modified diets on the types and levels of energy storage, and identify pathways comprising the regulatory network for energy homeostasis, including which organs sense and process food sources and physiological changes in energy levels. Specifically, these experiments aim to: (1) determine the effects of diet on the balance between intake (amount/type of food consumed) and usage (amount/type of energy stored); (2) address the role of the nervous system in regulating overall physiological energy balance and identify which specific regions of the brain are involved; and (3) identify inter-organ communication pathways responsible for maintaining the organism energy balance. Developing fruit flies will be fed modified diets and effects on levels of fat and other forms of energy storage, rates of food consumption, and overall growth and development will be assessed. To identify regions of the brain required for normal energy balance, genetically engineered flies will be used to ablate the function of specific groups of neurons and determine the effects on levels of fat stored and food ingested. Finally, a genome-wide screen will be performed to identify genes modifying fat storage and/or rates of food consumption. Knowledge of the diets and physiological conditions prone to inducing obesity will improve our understanding of this disorder and identify potential targets for both its treatment and prevention.