Integration of energy metabolism and the mammalian clock

Lin, Jiandie D.; Liu, Chang; Li, Siming

doi:10.4161/cc.7.4.5442

Cited by 49 publications

(39 citation statements)

References 79 publications

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“…These regulatory elements included FXR, the hormone adiponectin (AdipoQ), the nuclear retinoid X receptors RXRα and RXRβ, and the PPARs. PPARα is known to be regulated diurnally and interacts with regulators of circadian rhythm (Clock/Bmal1) (31). We observed that gastrointestinal BSH1 activity also promotes a significant shift in the expression pattern of genes normally regulated by circadian rhythm.…”

Section: Discussionmentioning

confidence: 81%

Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut

Joyce

MacSharry

Casey

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

500

431

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Alterations in the gastrointestinal microbiota have been implicated in obesity in mice and humans, but the key microbial functions influencing host energy metabolism and adiposity remain to be determined. Despite an increased understanding of the genetic content of the gastrointestinal microbiome, functional analyses of common microbial gene sets are required. We established a controlled expression system for the parallel functional analysis of microbial alleles in the murine gut. Using this approach we show that bacterial bile salt hydrolase (BSH) mediates a microbe-host dialogue that functionally regulates host lipid metabolism and plays a profound role in cholesterol metabolism and weight gain in the host. Expression of cloned BSH enzymes in the gastrointestinal tract of gnotobiotic or conventionally raised mice significantly altered plasma bile acid signatures and regulated transcription of key genes involved in lipid metabolism (Pparγ, Angptl4), cholesterol metabolism (Abcg5/8), gastrointestinal homeostasis (RegIIIγ), and circadian rhythm (Dbp, Per1/2) in the liver or small intestine. High-level expression of BSH in conventionally raised mice resulted in a significant reduction in host weight gain, plasma cholesterol, and liver triglycerides, demonstrating the overall impact of elevated BSH activity on host physiology. In addition, BSH activity in vivo varied according to BSH allele group, indicating that subtle differences in activity can have significant effects on the host. In summary, we demonstrate that bacterial BSH activity significantly impacts the systemic metabolic processes and adiposity in the host and represents a key mechanistic target for the control of obesity and hypercholesterolemia.

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Section: Discussionmentioning

confidence: 81%

Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut

Joyce

MacSharry

Casey

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

500

431

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“…The intrinsic nature of its highly specialized, temporally regulated transcription places the cellular clock as a prominent model for the study of dynamic chromatin remodeling. 38,39 Moreover, based on the tight coupling between circadian rhythms and metabolic regulation, 18 clock-controlled chromatin reorganization is likely to reveal specific pathways linking histone modifications to cellular metabolism. For example, the central clock protein Clock has histone acetyltransferase (HAT) enzymatic properties.…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned above, the ROR and Rev-erb families of orphan nuclear receptors couple metabolic functions to the clock oscillators by orchestrating these two systems simultaneously. 18 Other nuclear factors, including peroxisome proliferator-activated receptors (PPARs) and glucocorticoid receptor (GR), can serve as output regulators of the clock oscillators. 18 Second, metabolites can act as the integrators of clock and metabolism.…”

mentioning

confidence: 99%

“…18 Other nuclear factors, including peroxisome proliferator-activated receptors (PPARs) and glucocorticoid receptor (GR), can serve as output regulators of the clock oscillators. 18 Second, metabolites can act as the integrators of clock and metabolism. For example, intracellular carbon monoxide (CO) is generated endogenously by heme oxygenases during the catabolism of heme.…”

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confidence: 99%

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SWItch/sucrose nonfermentable (SWI/SNF) complex subunit BAF60a integrates hepatic circadian clock and energy metabolism

et al. 2011

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Many aspects of energy metabolism, including glucose and lipid homeostasis and mitochondrial oxidative metabolism, are under precise control by the mammalian circadian clock. However, the molecular mechanism for coordinate integration of the circadian clock and various metabolic pathways is poorly understood. Here we show that BAF60a, a chromatin-remodeling complex subunit, is rhythmically expressed in the liver of mice. Mice with liver-specific knockdown of BAF60a show abnormalities in the rhythmic expression pattern of clock and metabolic genes and in the circulating metabolite profile. Consistently, knockdown of BAF60a impairs the oscillation of clock genes in serum-shocked HepG 2 cells. At the molecular level, BAF60a activates Bmal1 and G6Pase transcription by way of the coactivation of retinoid-related orphan receptor alpha (RORa). In addition, BAF60a is present near ROR response elements (RORE) on the proximal Bmal1 and G6Pase promoters and turns the chromatin structure into the active state. Conclusion: Our data suggest a critical role for BAF60a in the coordinated regulation of hepatic circadian clock and energy metabolism in mammals. (HEPATOLOGY 2011;54:1410-1420 M any physiological events in mammals, including locomotor activity, sleep, blood pressure, circulating hormones, and energy metabolism show diurnal fluctuation. 1,2 These intrinsic biological rhythms are mainly entrained by light-dark (LD) and feeding cycles. The mammalian master clock resides in the hypothalamic suprachiasmatic nucleus (SCN) and drives slave oscillators distributed in various peripheral tissues through behavioral and neuroendocrine signals. However, Damiola et al. 3 found that peripheral oscillators can be uncoupled and reset from the central pacemaker by restricted feeding. Their findings are supported by the subsequent report showing that restricted feeding entrains the circadian rhythms in peripheral tissues, dominantly in the liver, but leaving SCN rhythms unaffected. 4 Also, both food availability and the temporal pattern of feeding determine the repertoire, phase, and amplitude of the circadian transcriptome in mouse liver. 5 All these studies indicate that nutritional signals play a dominant role in the regulation of peripheral clock function. At the molecular level, Clock and Bmal1 are two basic helix-loop-helix transcription factors that activate the transcription of period (Per) and cryptochrome (Cry) genes. 6 Per and Cry proteins in turn inhibit their own expression by repressing Clock/Bmal1 activity, forming the critical feedback loop within the clock circuitry. In addition, the orphan nuclear receptors of the ROR and Rev-erb families are also implicated in the control of circadian clock function. 7,8 Abbreviations: ChIP, chromatin immunoprecipitation; CO, carbon monoxide; CoIP, coimmunoprecipitation; GFP, green fluorescent protein; GR, glucocorticoid receptor; H3K4me3, trimethylation of lysine 4 of histone 3; H3K9me2, dimethylation of lysine 9 of histone 3; HAT, histone acetyltransferase; HDAC, histone deacetyla...

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“…The master clock in mammals is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and many physiological processes are subject to circadian oscillations, including lipid and carbohydrate metabolism, hormone secretion, and feeding behaviors (Eckel-Mahan and Sassone-Corsi 2013; Liu et al 2013;Adamovich et al 2014). In the liver, the circadian clock is closely related to the rhythmicity of hepatic metabolism (Lin et al 2008;Tahara and Shibata 2016). The autonomous rhythm of hepatocytes is entrained by not only the hormonal and neuronal signals from the master clock but also the nutrients and metabolites whose oscillation is in large part determined by feeding activity (Kornmann et al 2007;Feng and Lazar 2012).…”

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confidence: 99%

The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ

et al. 2017

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Liver lipid metabolism is under intricate temporal control by both the circadian clock and feeding. The interplay between these two mechanisms is not clear. Here we show that liver-specific depletion of nuclear receptors RORα and RORγ, key components of the molecular circadian clock, up-regulate expression of lipogenic genes only under fed conditions at Zeitgeber time 22 (ZT22) but not under fasting conditions at ZT22 or ad libitum conditions at ZT10. RORα/γ controls circadian expression of Insig2, which keeps feeding-induced SREBP1c activation under check. Loss of RORα/γ causes overactivation of the SREBP-dependent lipogenic response to feeding, exacerbating diet-induced hepatic steatosis. These findings thus establish ROR/INSIG2/SREBP as a molecular pathway by which circadian clock components anticipatorily regulate lipogenic responses to feeding. This highlights the importance of time of day as a consideration in the treatment of liver metabolic disorders.

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Integration of energy metabolism and the mammalian clock

Cited by 49 publications

References 79 publications

Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut

Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut

SWItch/sucrose nonfermentable (SWI/SNF) complex subunit BAF60a integrates hepatic circadian clock and energy metabolism

The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ

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