Metabolic disorders such as diabetes and obesity affect millions of people. Type 2 Diabetes (T2D) is the most common form of diabetes in which resistance to insulin signaling causes hyperglycemia and other complications. T2D is also correlated with circadian rhythm disruption, but the causative relationship is poorly understood. Increased O-linked glycosylation (O-GlcNAcylation) is a common link in the network between T2D and circadian rhythm. Typically, a portion of glucose is metabolized in the hexosamine biosynthetic pathway (HBP) and forms Uridine Diphosphate N-Acetyl Glucosamine (UDP-GlcNAc), a donor molecule for O- GlcNAcylation. Under homeostatic conditions, O-GlcNAcylation and phosphorylation are balanced and regulate protein activities. Thus, O-GlcNAcylation behaves as a glucose-sensitive regulator. Since hyperglycemia increases UDP-GlcNAc and O-GlcNAcylation levels, the resultant hyper-glycosylation can affect phosphorylation and modulate protein activity. Circadian rhythm and key clock proteins are tightly regulated by phosphorylation on a 24-hour cycle and disrupting this biochemical cycle correlates to metabolic disorders and depression. However, current evidence fails to describe mechanisms for T2D-induced circadian rhythm disruption. I propose to elucidate mechanisms of T2D-induced circadian rhythm disruption using genetic and metabolic approaches in a T2D fly model system with special focus on the posttranslational regulation of the circadian clock and clock kinases. I hypothesize that T2D will increase O-GlcNAcylation, reduce phosphorylation, and alter activities of specific proteins and kinases that modulate the clock. By investigating the role of O-GlcNAcylation in circadian clock regulation, new diagnostic profiles and therapeutic targets may be identified for the intervention of T2D risks, pathologies, and complications.
This project aims to characterize mechanisms by which metabolic disorders, specifically Type 2 Diabetes (T2D), affects circadian rhythm through central clock proteins and their regulatory kinases. O-linked glycosylation and phosphorylation are recognized as posttranslational mechanisms regulating circadian clock proteins, but interactions between these modifications are poorly understood. T2D and circadian clock disruption have several complications in common, but causative pathways have not been well characterized. Results from this project could identify mechanism by which T2D and metabolic disorders disrupt circadian clock regulation and lead to complications associated with T2D. These contributions may also help identify diagnostic profiles or therapeutic targets for intervening upon T2D pathologies, risks and complications induced by circadian clock disruption. This investigation will also contribute to a broader understanding of protein regulation through interactions between O-linked glycosylation and phosphorylation.
