Arda, H Efsun et al. (2009) International Worm Meeting "An Intricate Network of Nuclear Hormone Receptors Regulates Energy Balance in the Nematode C. elegans."

Doucette-Stamm, Lynn, Walhout, Albertha JM, Conine, Colin, Sequerra, Reynaldo, Taubert, Stefan, van Gilst, Marc, Yamamoto, Keith, Arda, H Efsun

[International Worm Meeting, 2009]

Obesity is a growing epidemic and results from an imbalanced energy homeostasis. Most metabolic genes are transcriptionally regulated, therefore deciphering the complex regulatory networks that govern energy homeostasis is crucial to understand the mechanisms underlying obesity. The nematode C. elegans is a powerful model organism to study metabolic transcriptional regulatory networks. Already ~400 genes have been identified that alter the body fat of the worm when inactivated, and an additional ~25 genes were shown to give transcriptional response upon fasting. In order to elucidate the transcriptional regulation of these "fat" and "fasting" genes, we mapped a transcription regulatory network using high-throughput, gene-centered yeast one-hybrid assays. This network contains numerous nuclear hormone receptor (NHR) type transcription factors, which are involved in fat metabolism throughout the Metazoa. We found that most of these previously uncharacterized NHRs partition into different modules based on the targets they share in the network. We show that several of them are necessary to maintain normal levels of body fat. Finally, we also found that many of the transcription factors identified in the fat network can interact with a mediator subunit, MDT-15, which is required for the regulation of fat metabolism both in C. elegans and mammalian systems. Taken together, our results provide an integrated network of transcriptional regulation of energy balance of C. elegans.