Metabolism drives all biological processes, dysregulation of which fuels a plethora of human diseases including diabetes, obesity, cancer, aging, cardiovascular and neurodegenerative diseases. The long-range goal of our research is to unravel temporal and spatial regulation of metabolic pathways in response to environmental and genetic cues, and to design strategies to battle metabolic diseases. Diet and the light/dark cycle are principle environmental cues that control intermediary metabolism. Nutrient flux into the cell triggers the posttranslational modification of intracellular proteins by the amino sugar called N-acetylglucosamine (O-GlcNAc). Our first goal is to elucidate how O-GlcNAc acts as a molecular switch that couples nutrient cues to cellular regulation of signal transduction, transcription and protein degradation. Both light and diet affect the body’s circadian rhythms. Our second goal is to depict molecular pathways that couple the circadian clock to metabolic physiology. We are employing a combination of experimental approaches, including biochemistry, molecular and cellular biology, mouse genetics, genomics, proteomics and metabolomics, to accomplish our research goals.
Extensive Research Description
The long-range goal of our research is to understand signaling and transcriptional mechanisms governing metabolism in response to environmental and genetic cues, and to design strategies to battle metabolic diseases.
Diet and the day/night cycle are principle environmental cues that control intermediary metabolism. Nutrient flux into the cell triggers protein modification by the amino sugar called N-acetylglucosamine (O-GlcNAc). This dynamic and reversible posttranslational modification is emerging as a key regulator of diverse cellular processes. Our first goal is to elucidate how O-GlcNAc acts as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. It is crucial to understand how perturbations in this posttranslational modification contribute to human diseases including diabetes, obesity, cancer and aging.
Both diet and light affect the body’s circadian rhythms. Our second goal is to unravel molecular links between the circadian clock and metabolic physiology. On the basis of our finding of broad expression and tissue-specific oscillation of nuclear receptors, we would like to determine potential roles of nuclear receptors in integrating circadian signals from nutritional cues and the light-sensing central clock to entrain peripheral clocks, and in coupling peripheral clocks to divergent metabolic outputs. There are the emerging links between circadian rhythm disorders and diabetes, obesity, and cardiovascular disease. We plan to explore novel strategies for treating these interrelated diseases.
To approach these goals, a combination of cutting-edge tools are employed, including biochemistry, molecular and cellular biology, mouse genetics, genomics, proteomics, metabolomics, and physiology.
Positions are available in my lab for highly motivated graduate students and postdoctoral fellows who are interested in exploring the frontier of research on metabolic physiology.
- Ruan H.B., M.O. Dietrich, Z.W. Liu, M.R. Zimmer, M.D. Li, J.P. Singh, K. Zhang, R. Yin, J. Wu, T.L. Horvath, X. Yang. O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 2014, 159:306–17.
- Li M.D., H.B. Ruan, M.E. Hughes, J.S. Lee, J.P. Singh, S.P. Jones, M.N. Nitabach, X. Yang. O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab. 2013, 17:303–10.
- Ruan H.B., X. Han, M.D. Li, J.P. Singh, K. Qian, S. Azarhoush, L. Zhao, A.M. Bennett, V.T. Samuel, J. Wu, J.R. Yates III, X. Yang. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1alpha stability. Cell Metab. 2012, 16:226-37.
- Yang X. A wheel of time: the circadian clock, nuclear receptors, and physiology. Genes & Dev. 2010, 24:741-7.
- Yang X., P.P. Ongusaha, P.D. Miles, J.C. Havstad, F. Zhang, W.W. So, J.E. Kudlow, R.H. Michell, J.M. Olefsky, S.J. Field, R.M. Evans. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 2008, 451:964-9.
- Yang X., M. Downes, R.T. Yu, A.L. Bookout, W. He, M. Straume, D.J. Mangelsdorf, R.M. Evans. Nuclear receptor expression links the circadian clock to metabolism. Cell 2006, 126:801-10.
- Yang X., F. Zhang, J.E. Kudlow. Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A: coupling protein O-GlcNAcylation to transcriptional repression. Cell 2002, 110:69-80