Functional Studies of Estrogen Related Receptors

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Project Summary Metabolic disorders have become an increasing burden for health worldwide as reflected by the unprecedented incidence of obesity and diabetes. The impact of these disorders on human health has refocused biomedical research on understanding the regulation of metabolism with a goal of developing new strategies for effective therapy. One of these efforts centers on nuclear receptors (NRs), which are a large family of ligand-regulated transcription factors that play central roles in development, growth and metabolism. In the Thummel laboratory, we utilize the model system Drosophila to discover evolutionarily-conserved aspects of NR regulation and function. My studies focus on the Estrogen-Related Receptors (ERRs) in maintaining metabolic homeostasis. Three paralogs make up the ERR family in mice and humans: ERRα, ERRβ, and ERRγ. Studies of these receptors have demonstrated their importance in regulating oxidative phosphorylation and mitochondrial function in energy-rich tissues. Our understanding of ERR functions, however, has been complicated by their overlapping expression patterns, genetic redundancy, and compensatory activities. Additionally, ERRα is necessary for lipid homeostasis in mammals; however, neither the tissue-specific nor mechanistic basis of this phenotype is well understood. In Drosophila, the ERR family is represented by a single ortholog, dERR, allowing us to study ERR functions in the absence of genetic redundancy. My project is focused on defining roles for dERR during the adult stage of life, when the animal maintains homeostasis in the context of energy expenditure to support the demands of motility and reproduction. My preliminary studies have shown that loss of dERR function in adults results in reduced fertility, decreased glycogen, and an almost complete lack of stored triglycerides. Transcriptional profiling by RNA-seq revealed that a number of genes involved in lipid metabolism are expressed at reduced levels in dERR mutants. My results support the hypothesis that dERR maintains lipid levels in adults through its roles in regulating lipid synthesis and lipid transport. I will test this hypothesis through two specific aims: (1) to characterize the tissue-specific functions of dERR and (2) to test the hypothesis that dERR maintains lipid synthesis and transport. Taken together, these studies exploit the rapid and powerful genetics of Drosophila to define the ancestral role of ERR in the absence of functional redundancy, provide new insights into how the mammalian receptors have diversified to exert their roles in metabolism, and establish a basis for understanding how misregulation of ERR-regulated pathways can contribute to metabolic disorders and human disease.