? 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 ? ?
