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      Retinoid acid-related orphan receptor γ, RORγ, participates in diurnal transcriptional regulation of lipid metabolic genes

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          Abstract

          The hepatic circadian clock plays a pivotal role in regulating major aspects of energy homeostasis and lipid metabolism. In this study, we show that RORγ robustly regulates the rhythmic expression of several lipid metabolic genes, including the insulin-induced gene 2a, Insig2a, elongation of very long chain fatty acids-like 3, Elovl3 and sterol 12α-hydroxylase, Cyp8b1, by enhancing their expression at ZT20-4. The time-dependent increase in their expression correlates with the rhythmic expression pattern of RORγ. The enhanced recruitment of RORγ to ROREs in their promoter region, increased histone acetylation, and reporter and mutation analysis support the concept that RORγ regulates the transcription of several lipid metabolic genes directly by binding ROREs in their promoter regulatory region. Consistent with the disrupted expression of a number of lipid metabolic genes, loss of ROR γ reduced the level of several lipids in liver and blood in a ZT-preferred manner. Particularly the whole-body bile acid pool size was considerably reduced in RORγ −/− mice in part through its regulation of several Cyp genes. Similar observations were made in liver-specific RORγ-deficient mice. Altogether, our study indicates that RORγ functions as an important link between the circadian clock and the transcriptional regulation of several metabolic genes.

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          Most cited references 46

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          Circadian integration of metabolism and energetics.

          Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.
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            Transcriptional architecture and chromatin landscape of the core circadian clock in mammals.

            The mammalian circadian clock involves a transcriptional feed back loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression, and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of messenger RNA (mRNA) cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling.
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              Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet.

              While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes' expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                15 September 2014
                20 August 2014
                20 August 2014
                : 42
                : 16
                : 10448-10459
                Affiliations
                [1 ]Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA
                [2 ]Collaborative Mass Spectrometry Group, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA
                [3 ]Department of Medicine, Colombia University, New York, NY 10032, USA
                Author notes
                [* ]To whom correspondence should be addressed. Tel: +1 919 541 2768; Fax: +1 919 541 4133; Email: jetten@ 123456niehs.nih.gov
                Article
                10.1093/nar/gku766
                4176349
                25143535
                Published by Oxford University Press on behalf of Nucleic Acids Research 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
                Page count
                Pages: 12
                Product
                Categories
                Gene regulation, Chromatin and Epigenetics
                Custom metadata
                15 September 2014

                Genetics

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