The goals set forth in this proposal address the role of the endogenous circadian clock in the regulation of metabolism, specifically, glucose and lipid homeostasis. Circadian rhythms are endogenously generated oscillations that take place in the course of a day. Environmental cues (zeitgebers) such as light and dark assist in the synchronization and maintenance of endogenous circadian rhythms, however, circadian rhythms are intrinsic, controlled at the cellular level by complex transcriptional feedback regulation by circadian clock genes including Clock, Bmall, Period and Cryptochrome. While the circadian system is in control of biological rhythms such as the sleep-wake cycle, hormone secretion, and body temperature, evidence is accumulating that there is a direct link between circadian rhythm and metabolism. Numerous transcriptional activators essential for metabolism (including the members of the nuclear receptor superfamily) appear to undergo circadian oscillations in metabolically active tissues. Furthennore, dismptions in circadian clock genes result in aberrations in lipid and glucose homeostasis as well as obesity. CLOCK, best known for its role as a circadian-regulating transcriptional activator, was recently discovered to have acetyltransferase activity, functioning as an enzyme to posttranslationally modify target proteins. The proposal set forth gives preliminary evidence that CLOCK binds to and posttranslationally modifies HNF-4a, a protein central to gluconeogenesis and cholesterol catabolism into bile acids. The central hypothesis of this proposal is that the binding of HNF-4a and its subsequent modification by circadian machinery is critical for nomnal glucose homeostasis. HNF-4a is essential for nomnal lipid and glucose metabolism as well as for normal pancreatic beta cell function. In fact, mutations in HNF-4a cause the early onset of type II diabetes, commonly referred to as maturity-onset diabetes of the young (MODY). Alterations in circadian rhythm produce profound disturbances in lipid and glucose homeostasis as well as body weight regulation. This phenotype begs the question of how exactly they function in metabolically active tissues. This proposal demonstrates ways in which CLOCK protein might impinge on metabolism in a manner which has not yet been considered, through direct interaction with and modification of HNF-4a. We would like to detemiine how the circadian system affects HNF-4a in the liver in order to understand why circadian disturbances can produce such profound changes in lipid metabolism and body weight regulation. This study may provide insight into how circadian clock machinery might be used in the future as a target for the conection or manipulation of glucose homeostasis in the body

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-W (O1))
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Castle, Arthur
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University of California Irvine
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