From a combination of genetic analyses and RNAi screening, we have discovered hundreds of gene inactivations and mutations that promise to reveal the neuroendocrine circuit through which C. elegans fat storage set points are determined. Because RNAi does not as potently target neurons, we have also configured classical genetic screens for low fat storage and high fat storage mutations. Some of the 80 mutants in our current collection store extraordinarily high levels of fat under all conditions tested whereas others have defects in the mobilization of fat induced by starvation or drug treatments. Interestingly, many of the mutants have defects in the behavioral outputs normally induced by starvation or satiety. Thus these mutants do not "feel" starved. We propose to molecular identify 5 of these top candidate mutants per year to discern their molecular identity as well as to delineate from their expression pattern which cells mediate the assessment of fat and the behaviors that drive fat storage. We will determine which of these gene inactivations affect fat levels by regulating rates of feeding and which affect gross metabolic levels. We will determine the cellular focus of gene activity for fat storage and whether any of the genes encode proteins that mediate the actual sorting of fats in the storage organs. From a gene array of starved and well fed animals, we have also discovered a number of genes that are induced by starvation or by feeding. GFP fusions to these genes have generated a robust set of reporters of the starved state. We will cross these reporter genes into our mutant collection to assess which mutants induce a starved state and which do not. In addition, we have used these reporter genes already in a classical genetic screen for mutants that fail to induce a starvation marker gene. C. elegans is amenable to large scale genetic and functional genomic screens which is not feasible in mice. Our worm genomics highlights scores of human genes which are homologues of the worm genes we have identified. In some cases, the genes encode proteins that are attractive for the development of drugs. Therefore, identification of fat storage pathway genes in C. elegans provides targets for intervention of human obesity.
Our C. elegans gene inactivation analysis has revealed hundreds of genes that regulate of fat storage, many of which have human homologues. The studies of obesity in C. elegans is likely to identify targets for intervention of obesity in human.
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