Genes mediating glucopenia-induced obesity in nematodes

描述(由申请人提供)： 这项拟议研究的长期目标是发现调节人类肥胖发展的基因。一些证据表明，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会导致肥胖。例如，葡萄糖类似物2-脱氧葡萄糖(2-DG)减弱了葡萄糖感应系统(葡萄糖减少症)，显著降低了哺乳动物的代谢率，增加了摄食量。然而，在哺乳动物中，调节葡萄糖对体重调节作用的分子机制一直很难研究，而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在线虫中产生迅速而显著的肥胖。因此，拟议的研究将使用线虫中的RNAi来系统地筛选其消融阻止2-DG诱导的肥胖的基因，特别关注在哺乳动物和线虫中具有同源性的基因。具体目标1将评估切除介导神经内分泌调节的特定基因(G蛋白偶联受体和配体调节的离子通道)是否会阻止血糖减少诱导的肥胖。特定目标2将评估低血糖诱导的特定基因在小鼠下丘脑中的消融是否能阻止葡萄糖减少诱导的肥胖。具体目标3将评估去除饮食诱导肥胖小鼠组织中诱导的特定基因是否会阻止血糖减少诱导的肥胖。特定目标4将评估在血糖减少诱导的肥胖中前三个特定目标所涉及的基因的消融是否会阻止其他形式的肥胖(Daf-2等)。在线虫中。相反，特殊目标4还将评估切除线虫中与其他形式肥胖有关的基因是否会阻止血糖减少诱导的肥胖。尤其令人感兴趣的将是那些在标准条件下消融不会产生明显表型的基因，但它们的消融可以阻止葡萄糖减少症诱导的肥胖。这些研究将为减肥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