Genomic analysis of C. elegans fat regulatory pathways

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DESCRIPTION (provided by applicant): We have tested thousands of genes in the C. elegans worm and have discovered hundreds of promising candidates that may determine how fat is stored and used in a variety of animals. We identified about 300 worm genes that when inactivated decrease fat content and about 100 genes that when inactivated caused increased fat storage. This list of 400 genes constitutes the metabolism and communications pathway that controls how much fat is stored in an animal body. The identified genes were very diverse, including both the expected genes involved in fat and cholesterol metabolism as well as other new candidates, including some that are expected to function in the central nervous system. About half of the fat regulatory genes have counterparts in humans and other mammals. Thus, of the estimated 30,000 human genes, our worm genomics highlights about 200 genes as likely to play key roles in regulation of fat levels. In some cases, the genes encode proteins that are attractive for the development of drugs. The mammalian tub gene encodes an evolutionary conserved protein that is highly expressed in the central nervous system, notably in the hypothalamus, a center of feeding control. Loss of function mutations in tublead to late-onset obesity, retinal degeneration and hearing loss. The worm ortholog of tubby is also expressed in ciliated sensory neurons. To better understand the molecular function of tub will clearly require the identification of additional genes that act in the pathway with tub. These tub pathway genes may mediate tub function in the nervous system or act distally in peripheral tissues to affect energy balance and fat metabolism in response to neuronal tub activity. There is a single tub homologue in C. elegans, thus avoiding complications from functional redundancy when multiple gene family members are present. More importantly, C. elegans is amenable to large scale genetic and functional genomic screens which is not feasible in mice. Therefore, identification of tub pathway genes in C. elegans may provide targets for intervention of obesity in human.