1、读书汇报： Metabolism and Circadian Rhythms Implications for Obesity The prevalence of obesity is taking on enormous proportions. Obesity is defined by the World Health Organisation as the accumulation of excessive fat tissue, to the point that it may impair health. Circadian rhythms are an important reg
2、ulator of many key biological processes that influence cellular metabolic pathways and organ function . The results from a series of studies have demonstrated the importance of normal circadian action for maintaining health in people and the disruption of circadian rhythm , which can have adverse ef
3、fects on metabolic function. obesity circadian rhythms energy metabolism Metabolism and Circadian Rhythms Implications for Obesity The Biological Clock The location of the mammalian biological clock Regulation of rhythms SCN efferents and afferents The biological clock at the molecular level The Bio
4、logical Clock and Obesity Effect of circadian rhythms on lipid metabolism Effect of high-fat diet on circadian rhythms Oren Froy Israel Endocrine Reviews, February 2010, IF:19.929 The Biological Clock The Biological Clock have a 24 h cycle, persist in the absence of environmental cues, adjust to mat
5、ch local time (so-called entrainment) and maintain intrinsic periodicity over a range of physiological temperatures . In mammals, the central circadian clock is located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus in the brain. The SCN clock is composed of multiple single-cell ci
6、rcadian oscillators, which, when synchronized, generate coordinated circadian outputs that regulate overt rhythms Metabolism and Circadian Rhythms Implications for Obesity The Biological Clock The location of the mammalian biological clock Regulation of rhythms SCN efferents and afferents The biolog
7、ical clock at the molecular level The Biological Clock and Obesity Effect of circadian rhythms on lipid metabolism Effect of high-fat diet on circadian rhythms Oren Froy Israel Endocrine Reviews, February 2010, IF:19.929 下丘脑背内侧核 SCN efferents and afferents The biological clock at the molecular level
8、 The clock is an intracellular mechanism sharing the same molecular components in SCN neurons and peripheral cells. Transcriptional-translational feed-back loops lie at the very heart of the core clock mechanism. Many clock gene products function as transcription factors that possess PAS (PER, ARNT,
9、 SIM) and basic helix-loop-helix domains involved in protein-protein and protein-DNA interactions. The genes encoding the core clock mechanisms include circadian locomotor output cycles kaput ( Clock), brain and muscle-Arnt-like 1 (Bmal1 ), Period1 (Per1 ), Period2 (Per2), Period3 (Per3 ), Cryptochr
10、ome1 (Cry1), and Cryptochrome2 (Cry2 ). Cellular time keeping Metabolism and Circadian Rhythms Implications for Obesity The Biological Clock The location of the mammalian biological clock Regulation of rhythms SCN efferents and afferents The biological clock at the molecular level The Biological Clo
11、ck and Obesity Effect of circadian rhythms on lipid metabolism Effect of high-fat diet on circadian rhythms Oren Froy Israel Endocrine Reviews, February 2010, IF:19.929 The Biological Clock and Obesity Effect of circadian rhythms on lipid metabolism Circadian clocks have been shown to be present in
12、WAT, and brown adipose tissue. Recent transcriptome studies revealed rhythmic expression of clock and adipokine genes, such as resistin, adiponectin, and visfatin, in visceral fat tissue. Fatty acid transport protein 1 ( Fatp1), fatty acyl-CoA synthetase 1 (Acs1) , and adipocyte differentiation-rela
13、ted protein ( Adrp) exhibit diurnal variations in expression, suggesting that nocturnal expression of FATP1, ACS1, and ADRP will promote higher rates of fatty acid uptake and storage of triglyceride in rodents . Company Logo BMAL1 activity in the control of adipogenesis and lipid metabolism BMAL1 a
14、ctivity Loss of BMAL1 expression led to a significant decrease in adipogenesis and gene expression of several key adipogenic/lipogenic factorsPPAR 2, adipocyte fatty acid-binding protein 2 (aP2). Bmal1 / knockout mice Overexpression of BMAL1 in adipocytes increased lipid synthesis activity. Overexpr
15、e-ssion of BMAL1 This proadipogenic transcription factor, whose levels increase dramatically during adipocyte differentiation, exhibits striking diurnal variations in expression in murine adipose tissue and rat liver. In addition to its role in lipid metabolism and adipocyte differentiation, REV-ERB
16、 is a negative regulator of Bmal1 expression. The interconnection between the clock core mechanism and lipogenic and adipogenic pathways emphasizes why clock disruption leads to metabolic disorders. Effect of high-fat diet on circadian rhythms Recent studies have shown that introduction of a high-fa
17、t diet to animals leads to rapid changes in both the period of locomotor activity in constant darkness and to increased food intake during the normal rest period under light-dark conditions. These changes in behavioral rhythmicity correlated with disrupted clock gene expression within hypothalamus,
18、liver, and adipose tissue, as well as with altered cycling of hormones and nuclear hormone receptors involved in fuel utilization, such as leptin, TSH, and testosterone in mice, rats, and humans. AMPK has been found to phosphorylate Ser-389 of CKI, resulting in increased CKI activity and degradation
19、 of mPER2. mPER2 degradation leads to a phase advance in the circadian expression pattern of clock genes in wild-type mice . As the levels of mAMPK decline under a high-fat diet , it is plausible that the changes seen in the expression phase of genes under a high-fat diet are mediated by changes in
20、AMPK levels. conclusion However, further study is required in order to fully understand the intricate relationships between the circadian clock and metabolism. This understanding may lead to the resetting of the circadian clock leading, in turn, to better functionality of physiological systems, prevention of metabolic disorders and promotion of well-being. THE END
