? Obesity afflicts millions of Americans and other people worldwide. The health problems associated with obesity are rising at epidemic rates, challenging world health care system to provide adequate care. The long-term goal of our research is to dissect the pathways of fat regulation to better understand the mechanisms by which interactions among specific genes act to either promote or facilitate resistance to obesity. Our genome-wide RNAi screen has identified 400 genes that, when inactivated, affect fat storage in C. elegans. We have also identified several C. elegans genes that influence obesity-related phenotypes. Mutant strains with reduced stearoyl-CoA desaturase (SCO) activity have reduced fat stores and the reduced ability to withstand periods of starvation when compared to wild type. Stearoyl-CoA desaturase is a key lipogenic enzyme that catalyzes the biosynthesis of monounsaturated fatty acids from saturated fatty acids. We intend to further characterize the SCO mutants, to determine which metabolic pathways are affected by the loss or reduction of this activity, and to further characterize regulators of SCO activity, including the nuclear hormone receptor nhr-80 and SREBP. In order to identify the metabolic and regulatory pathways that are affected by SCO, we will (1) use genome-wide RNAi screens to identify suppressors of the low fat phenotype of SCO-deficient strain, (2) examine the expression of a panel of metabolic genes in SCO deficient strains, as well as in mutants of regulators of SCO, and (3) use genome-wide approaches to identify genes necessary for the correct processing of C. elegans SREBP and to identify genes regulated by this central regulator of lipid homeostasis. C. elegans is amenable to large scale genetic and functional genomic screens that are not feasible in other systems. Using our collection of mutants and the powerful genetic and genomic resources available in C. elegans, we are now poised to provide a new level of understanding of the specific pathways affected by the stearoyl-CoA desaturases and their transcriptional activators in fat storage and metabolism ? ?
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