Regulation of fatty acid metabolism by the nuclear receptor DHR78. Stefanie M. Marxreiter, Carl S. Thummel. Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT.

   DHR78 encodes the single fly ortholog of the mammalian orphan nuclear receptors TR2 and TR4. Previous studies of DHR78 mutants showed a severe developmental defect where larvae fail to molt their trachea correctly and display roving behavior, reduced growth, and eventually die as third instars. A recent paper described a similar phenotype in animals lacking acetyl-CoA-carboxylase (ACC), which acts as the rate-limiting step in fatty acid synthesis (Parvy et al. (2012) PLoS Genetics 8: e1002925). Consistent with this observation, Northern blot analysis revealed that ACC expression is significantly reduced in DHR78 mutants. Moreover, recent studies of TR4 mutant mice indicate that it regulates a metabolic transcriptional program, including many genes involved in lipid metabolism. These animals are also protected against obesity when fed a high-fat diet. Antibody staining revealed that DHR78 is not only expressed in the trachea, but is also expressed in key metabolic tissues such as the midgut and fat body. Triacylglycerol (TAG) and glycogen assays combined with Oil Red O staining revealed significant reductions in stored energy in DHR78 mutant larvae. Current efforts are focused on using tissue-specific genetic rescue experiments, metabolomics, and RNA-seq to define the role of DHR78 in metabolism and growth.