Our overall objective is to elucidate the mechanisms that control adipocyte development and function. The ability to store energy, primarily as fat, is a fascinating property that seems to be required for the life cycle of many higher organisms. Unfortunately, abnormalities in fat accumulation produce pathological states including obesity, which is rapidly becoming one of the major causes of morbidity and mortality throughout the world. Yet, the genes that regulate adipocyte development and physiology are not fully understood. Invertebrates have proven to be powerful tools for gene discovery and for characterizing gene function. So, it would be great to have an invertebrate model for fat development. We have encouraging preliminary data that suggests that C. elegans fat might be such a model and we propose to test and exploit these initial observations. ? The specific experimental aims are: I. To study genes we identified as necessary for C. elegans fat formation. We will characterize the genes in both living worms and mammalian systems. II. To characterize the transcriptional profile of C. elegans fat with microarrays. We will compare the expression profiles of wild-type worms and worms that lack fat stores. Then, we will analyze the salient genes in worms and in mammalian systems. Ill. To identify genes required for formation of C. elegans fat via reverse and forward genetic screens. We will generate worms that lack fat by altering gene function with RNAi and with EMS mutagenesis. Then, we will characterize the responsible genes. Our long-term goal is to understand mammalian adipogenesis with the hope that understanding genes and mechanisms can lead to rational and effective treatments to relieve the suffering associated with obesity and diabetes. ? ?
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