The effects of metabolic dysfunction on phosphoregulation of the circadian clock

University Of California At Davis, Davis CA

Investigators

Abstract

DESCRIPTION (provided by applicant): 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.