Genes mediating glucopenia-induced obesity in nematodes

这项拟议研究的长期目标是发现调节糖尿病发展的基因。 人类的肥胖。多条证据表明，对神经内分泌效应敏感的神经元 葡萄糖调节体重，这意味着这些葡萄糖感应机制的减弱可能导致 肥胖。例如，葡萄糖类似物2-对葡萄糖传感系统(血糖减少症)的衰减。 脱氧葡萄糖(2-DG)能显著降低哺乳动物的代谢率，增加摄食量。然而， 调节葡萄糖对体重调节作用的分子机制一直很难 在哺乳动物身上进行研究，在很大程度上还不清楚。幸运的是，2-DG在体内产生肥胖表型 哺乳动物，在线虫身上会迅速产生惊人的肥胖症。因此，拟议的研究将使用RNAi 线虫系统筛选其消融阻断2-DG诱导的肥胖的基因，重点 特别是在哺乳动物和线虫中具有同源性的基因。特定目标1将评估是否 去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- 受调节的离子通道)将阻止由血糖减少引起的肥胖。特殊目标2将评估消融是否 小鼠下丘脑低血糖诱导的特定基因将阻止葡萄糖减少诱导的肥胖。 特定目标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 阻止糖耐量减少引起的肥胖。特定目标4将评估前三项所涉及的基因的消融 针对血糖减少引起的肥胖的特定目标将阻止其他形式的肥胖(Daf-2等)。在线虫中。 相反，特殊目标4也将评估是否消融与其他形式的肥胖有关的基因。 雅致将阻止由血糖减少引起的肥胖。尤其令人感兴趣的是基因的消融不会 在标准条件下产生明显的表型，但其消融可阻断糖皮质激素减少症 肥胖。这些研究将为减肥药物的潜在靶点提供建议。

The long-term objectives of the proposed studies is 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.