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말초조직 일주기성이 에너지 대사 조절에 미치는 역할 규명
Roles of peripheral circadian clock in the regulation of energy metabolism

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Authors
장하군
Advisor
김재범
Major
자연과학대학 생명과학부
Issue Date
2016-02
Publisher
서울대학교 대학원
Keywords
obesitydiabetescircadian clockSREBP1cCRY1FOXO1MDM2PEPCKG6PaseHepatic gluconeogenesisinsulin siganling
Description
학위논문 (박사)-- 서울대학교 대학원 : 생명과학부, 2016. 2. 김재범.
Abstract
Emerging evidence has suggested that the circadian clock is a control tower in the regulation of behavioral and molecular processes under day/night cycle. Also, precise regulation of the circadian clock is crucial for maintaining whole-body energy homeostasis. Thus, dysregulation of the circadian clock is closely associated with obesity and metabolic complications. In metabolic organs, such as adipose tissue, muscle and liver, the circadian clocks affect various metabolic processes including lipogenesis, gluconeogenesis and lipid oxidation. Moreover, unsynchronized cooperation between the hypothalamic central clock and the peripheral clock, in shift workers, is prone to occur metabolic disorders. However, the pathophysiological role of the circadian clock and its metabolic regulatory processes have not been thoroughly elucidated.
In this study, I have demonstrated that unsynchronized circadian clock influences hepatic glucose and lipid metabolisms without altering body weight. With the same amounts of caloric intake during different time periods, the expression patterns of peripheral circadian clock genes showed different by day time feeding and night time feeding, while that of light-regulated hypothalamic circadian clock genes was not affected. For instance, the expression pattern of core circadian clock genes, such as BMAL1, CLOCK and PER2 in peripheral tissues, was altered by different feeding periods. In addition, hepatic expression of lipogenic genes, gluconeogenic genes, and fatty acid oxidation genes was also changed by feeding periods. In conclusion, it is likely that the amounts of food consumed might be a crucial factor to induce obesity compared to feeding time because feeding period restriction has no effects on body weight gain either normal chow diet (NCD) or high fat diet (HFD).
In addition, I have revealed that feeding-induced CRY1 gene expression leads to suppression of hepatic gluconeogenesis. Given that SREBP1c is a well-known transcriptional activator in postprandial state for activating lipogenesis, I found out that SREBP1c stimulated CRY1 gene expression. CRY1 was induced by feeding and insulin challenge. In addition, I have shown that hepatic SREBP1c contributed to repress gluconeogenesis through CRY1 induction. Hepatocytes overexpressing CRY1 inhibited hepatic gluconeogenic genes, such as PEPCK and G6Pase, via lowering FOXO1 protein. Furthermore, CRY1 was elevated in long term insulin action for sustainable suppression of hepatic gluconeogenesis. Intriguingly, SREBP1c-induced CRY1 accelerated FOXO1 degradation via ubiquitination. I discovered that CRY1 would act as a scaffold protein by binding with MDM2, an E3 ubiquitin ligase, and FOXO1. Although SREBP1c is increased in obese diabetic animals, such as db/db mice and HFD fed mice, SREBP1c failed to stimulate CRY1 and thereby hepatic gluconeogenesis was not suppressed in obese animals. When I overexpressed CRY1 in the liver of db/db mice to test the CRY1 effects on gluconeogenesis suppression. CRY1 overexpression reduced blood glucose level as well as downregulated hepatic gluconeogenic gene expression. Taken together, these data suggest that circadian clock genes actively and dynamically regulate energy metabolism in the liver. Among many circadian clock genes, SREBP1c-induced CRY1 especially contributes to the suppression of hepatic glucose production through FOXO1 degradation in liver. However, body weight gain is mainly determined by the amounts of calorie intake rather than alteration of peripheral circadian clock gene. Therefore, it is likely that appropriate regulation of SREBP1c-CRY1 signaling pathway would be crucial for maintaining whole-body energy homeostasis.
Language
English
URI
https://hdl.handle.net/10371/121437
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College of Natural Sciences (자연과학대학)Dept. of Biological Sciences (생명과학부)Theses (Ph.D. / Sc.D._생명과학부)
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