Genes mediating glucopenia-induced obesity in nematodes

描述（由申请人提供）： 这些研究的长期目标是发现介导人类肥胖发展的基因。有证据表明，对葡萄糖的神经内分泌效应敏感的神经元调节体重，这意味着这些葡萄糖感知机制的减弱可能导致肥胖。例如，葡萄糖类似物2-脱氧葡萄糖（2-DG）对葡萄糖传感系统（葡萄糖减少症）的衰减强烈降低了哺乳动物的代谢率并增加了摄食。然而，调节葡萄糖对体重调节作用的分子机制在哺乳动物中很难研究，并且在很大程度上还不清楚。幸运的是，在哺乳动物中产生肥胖表型的2-DG在C.优雅因此，拟议的研究将在C中使用RNAi。elegans系统地筛选基因的消融块2-DG诱导的肥胖，特别是在哺乳动物和C.优雅具体目标1将评估介导神经内分泌调节（G蛋白偶联受体和配体调节离子通道）的特定基因的消融是否会阻断葡萄糖减少诱导的肥胖。具体目标2将评估小鼠下丘脑中由低血糖诱导的特定基因的消融是否会阻断葡萄糖减少诱导的肥胖。具体目标3将评估在具有饮食诱导的肥胖的小鼠组织中诱导的特定基因的消融是否会阻断葡萄糖减少诱导的肥胖。具体目标4将评估在葡萄糖减少诱导的肥胖症中前三个具体目标所涉及的基因的消融是否会阻断其他形式的肥胖症（Daf-2等）。in C.优雅相反，Specific Aim 4还将评估是否消除与C中其他形式的肥胖有关的基因。elegans将阻止葡萄糖减少诱导的肥胖。特别感兴趣的是在标准条件下消融不产生明显表型，但消融阻断葡萄糖减少诱导的肥胖的基因。这些研究将为抗肥胖药物提供潜在的靶点

DESCRIPTION (provided by applicant): The long-term objectives of the proposed studies are to discover genes that mediate the development of obesity in humans. Several lines of evidence suggest that neurons sensitive to the neuroendocrine effects of glucose regulate body weight, implying that attenuation of these glucose-sensing mechanisms could cause obesity. For example, attenuation of glucose sensing systems (glucopenia) by the glucose analog 2- deoxyglucose (2-DG) robustly decreases metabolic rate and increases feeding in mammals. However, molecular mechanisms mediating the effects of glucose on body weight regulation have been difficult to study in mammals and are largely not understood. Fortunately, 2-DG, which produces obese phenotypes in mammals, produces rapid and striking obesity in C. elegans. The proposed studies will therefore use RNAi in C. elegans to systematically screen for genes whose ablation blocks 2-DG-induced obesity, focusing specifically on genes which have homologs in both mammals and C. elegans. Specific Aim 1 will assess if ablation of specific genes mediating neuroendocrine regulation (G protein coupled receptors and ligand- regulated ion channels) will block glucopenia-induced obesity. Specific Aim 2 will assess if ablation of specific genes induced by hypoglycemia in mouse hypothalamus will block glucopenia-induced obesity. Specific Aim 3 will assess if ablation of specific genes induced in mouse tissues with diet-induced obesity will block glucopenia-induced obesity. Specific Aim 4 will assess if ablation of genes implicated by the first three Specific Aims in glucopenia-induced obesity will block other forms of obesity (Daf-2, etc.) in C. elegans. Conversely, Specific Aim 4 will also assess if ablation of genes implicated in other forms of obesity in C. elegans will block glucopenia-induced obesity. Of particular interest will be genes whose ablation does not produce an obvious phenotype in standard conditions, but whose ablation blocks glucopenia-induced obesity. These studies will suggest potential targets for anti-obesity drugs