Metabolic syndrome is a result of the disturbance of metabolic homeostasis by complex interactions between genes and the environment. It has yet to be answered whether there is a unifying pathophysiology for metabolic syndrome. Investigators have looked into specific genetic and environmental factors involved in this medical condition. This "reductionist" approach may be ineffective to uncover the central mechanism(s) of the syndrome because metabolic homeostasis is a multifaceted and dynamic process. To this end, it would be critical to discover the molecular underpinnings that integrate systemic and dynamic variations in metabolism. Nutrient flux through the hexosamine biosynthetic pathway leads to the posttranslational modification of cytoplasmic and nuclear proteins by O-linked 2-N-acetylglucosamine (O-GlcNAc). This dynamic and reversible process involves two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), by which O-GlcNAc is attached to and removed from proteins, respectively. Growing evidence points to a pivotal role for O-GlcNAc in insulin signaling and metabolic regulation. Our recent work has shown that overexpression of either OGT or OGA in liver produces insulin resistance and dyslipidaemia. This surprising finding suggests that balanced O-GlcNAc levels are critical for metabolic homeostasis. Our central hypothesis is that O-GlcNAc serves as a key sensor and regulator of systemic homeostasis that links nutrient excess to metabolic syndrome. On the basis of our recent observation that O-GlcNAc is markedly disturbed in adipose tissue of mouse models of metabolic syndrome, we propose to investigate the contribution of O-GlcNAc in adipose tissue to the pathogenesis of metabolic syndrome and to delineate regulatory mechanisms for O-GlcNAc function in metabolism. We will accomplish these goals by executing the following Specific Aims:
In Aim 1, we will determine changes in O-GlcNAc signaling in diet- and genetic-induced mouse models of metabolic syndrome.
In Aim 2, we will test whether genetic intervention of O-GlcNAc in adipose tissue ameliorates metabolic defects in the mouse model of metabolic syndrome.
Aim 3 will explore the regulation of OGT and OGA by posttranslational modifications. Understanding the impact of this regulatory switch on metabolic physiology shall lay a foundation for exploring O-GlcNAc as a therapeutic target for metabolic syndrome.
Metabolic syndrome affects at least 20% of the population in the United States, becoming one of the principal threats to human health in the twenty-first century. Completion of this proposal will establish the pathophysiological and mechanistic links between O-GlcNAc signaling and systemic metabolic homeostasis. Pharmacological intervention to reset O-GlcNAc levels may represent an innovative strategy for preventing and treating metabolic syndrome.
|Singh, Jay Prakash; Zhang, Kaisi; Wu, Jing et al. (2015) O-GlcNAc signaling in cancer metabolism and epigenetics. Cancer Lett 356:244-50|
|Ruan, Hai-Bin; Dietrich, Marcelo O; Liu, Zhong-Wu et al. (2014) O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat. Cell 159:306-17|
|Wu, Jing; Bowe, Damon B; Sadlonova, Andrea et al. (2014) O-GlcNAc transferase is critical for transducin-like enhancer of split (TLE)-mediated repression of canonical Wnt signaling. J Biol Chem 289:12168-76|
|Lee, Yoonjin; Dominy, John E; Choi, Yoon Jong et al. (2014) Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. Nature 510:547-51|
|Li, Min-Dian; Ruan, Hai-Bin; Hughes, Michael E et al. (2013) O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab 17:303-10|
|Li, Min-Dian; Ruan, Hai-Bin; Singh, Jay P et al. (2012) O-GlcNAc transferase is involved in glucocorticoid receptor-mediated transrepression. J Biol Chem 287:12904-12|
|Diano, Sabrina; Liu, Zhong-Wu; Jeong, Jin Kwon et al. (2011) Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat Med 17:1121-7|