Real-time recording of circadian liver gene expression in freely moving mice reveals the phase-setting behavior of hepatocyte clocks

Saini, Camille; Liani, André; Curie, Thomas; Gos, Pascal; Kreppel, Florian; Emmenegger, Yann; Bonacina, Luigi; Wolf, Jean‐Pierre; Poget, Yves Alain; Franken, Paul; Schibler, Ulrich

doi:10.1101/gad.221374.113

Cited by 135 publications

(214 citation statements)

References 50 publications

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“…S1 F-I). Of note, using luciferase reporter mice, Saini et al (8) observed a similar pattern of expression for Per2, RevErbα, and Bmal1 in RF livers. That early RF metabolic changes were similar to those generated under starvation and that RF and starvation altered the same CC components prompted us to investigate how metabolic alterations may impair PCC during RF.…”

Section: Resultsmentioning

confidence: 72%

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

Mukherji

Kobiita

Chambon

2015

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

104

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The molecular mechanisms underlying the events through which alterations in diurnal activities impinge on peripheral circadian clocks (PCCs), and reciprocally how the PCCs affect metabolism, thereby generating pathologies, are still poorly understood. Here, we deciphered how switching the diurnal feeding from the active to the rest phase, i.e., restricted feeding (RF), immediately creates a hypoinsulinemia during the active phase, which initiates a metabolic reprogramming by increasing FFA and glucagon levels. In turn, peroxisome proliferator-activated receptor alpha (PPARα) activation by free fatty acid (FFA), and cAMP response element-binding protein (CREB) activation by glucagon, lead to further metabolic alterations during the circadian active phase, as well as to aberrant activation of expression of the PCC components nuclear receptor subfamily 1, group D, member 1 (Nr1d1/RevErbα), Period (Per1 and Per2). Moreover, hypoinsulinemia leads to an increase in glycogen synthase kinase 3β (GSK3β) activity that, through phosphorylation, stabilizes and increases the level of the RevErbα protein during the active phase. This increase then leads to an untimely repression of expression of the genes containing a RORE DNA binding sequence (DBS), including the Bmal1 gene, thereby initiating in RF mice a 12-h PCC shift to which the CREB-mediated activation of Per1, Per2 by glucagon modestly contributes. We also show that the reported corticosterone extraproduction during the RF active phase reflects an adrenal aberrant activation of CREB signaling, which selectively delays the activation of the PPARα-RevErbα axis in muscle and heart and accounts for the retarded shift of their PCCs.shifted eating | shifted peripheral circadian clocks | metabolic alterations | RevErbα | PPARα P ioneering studies (1, 2) have established that switching the feeding time in mice from the "active" phase [dark period of the light-dark (L/D) cycle] to the "rest" phase (light period), i.e., restricted feeding (RF), overrides the suprachiasmatic nucleus (SCN) circadian clock (CC)-derived signals and acts as a "zeitgeber" for peripheral CCs (PCCs), leading to a 12-h shift in the time at which components of PCCs are expressed. Numerous studies have shown that under homeostatic conditions, the functions of PCCs and metabolism are tightly linked and that perturbations in their interactions leads to pathologies, e.g., obesity and metabolic syndrome (3-5).The identity of some of the molecular pathways that couple PCCs to metabolism are known (3-5), but it is largely unknown how environmental cues, e.g., altered feeding schedules, may directly perturb the expression of individual CC components (5-7), thereby leading to obesity and a metabolic syndrome-like pathology (5). Assuming that specific metabolic perturbations generated by switching the feeding time could selectively affect the time of expression of some of the CC core components, we looked for both metabolic and PCC alterations at early RF times. We report here a comprehensive temporal analysis, an...

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Section: Resultsmentioning

confidence: 72%

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

Mukherji

Kobiita

Chambon

2015

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

104

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“…Adenovirus mediated gene transfer is widely used to modulate the expression of genes in the liver and known to primarily transduce hepatocytes (51)(52)(53)(54)(55). However, the method has limitations that adenovirus will be cleared by host immune cells and will not sustain the transduction.…”

Section: Discussionmentioning

confidence: 99%

Liver Perilipin 5 Expression Worsens Hepatosteatosis But Not Insulin Resistance in High Fat-Fed Mice

Trevino

Mazur-Hart

Machida

et al. 2015

Molecular Endocrinology

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Perilipin 5 (PLIN5) is a lipid droplet (LD) protein highly expressed in oxidative tissues, including the fasted liver. However, its expression also increases in nonalcoholic fatty liver. To determine whether PLIN5 regulates metabolic phenotypes of hepatosteatosis under nutritional excess, liver targeted overexpression of PLIN5 was achieved using adenoviral vector (Ad-PLIN5) in male C57BL/6J mice fed high-fat diet. Mice treated with adenovirus expressing green fluorescent protein (GFP) (Ad-GFP) served as control. Ad-PLIN5 livers increased LD in the liver section, and liquid chromatography with tandem mass spectrometry revealed increases in lipid classes associated with LD, including triacylglycerol, cholesterol ester, and phospholipid classes, compared with Ad-GFP liver. Lipids commonly associated with hepatic lipotoxicity, diacylglycerol, and ceramides, were also increased in Ad-PLIN5 liver. The expression of genes in lipid metabolism regulated by peroxisome proliferator-activated receptor-α was reduced suggestive of slower mobilization of stored lipids in Ad-PLIN5 mice. However, the increase of hepatosteatosis by PLIN5 overexpression did not worsen glucose homeostasis. Rather, serum insulin levels were decreased, indicating better insulin sensitivity in Ad-PLIN5 mice. Moreover, genes associated with liver injury were unaltered in Ad-PLIN5 steatotic liver compared with Ad-GFP control. Phosphorylation of protein kinase B was increased in Ad-PLIN5-transduced AML12 hepatocyte despite of the promotion of fatty acid incorporation to triacylglycerol as well. Collectively, our data indicates that the increase in liver PLIN5 during hepatosteatosis drives further lipid accumulation but does not adversely affect hepatic health or insulin sensitivity.

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“…Many studies have shown that also the peripheral clocks show daily rhythms, but the coherency of these rhythms seems to depend strongly on the SCN as some studies showed that peripheral tissues lost their daily rhythmicity after an SCN lesion (Akhtar et al 2002;Sakamoto et al 1998;Yoo et al 2004;Yamazaki et al 2000). However, more recent studies Saini et al 2013;Tahara et al 2012) showed that the peripheral clock genes may maintain their daily rhythmicity, although with a different amplitude, after an SCN lesion. These recent findings indicate that the rhythms of peripheral clocks apparently can also be synchronized with the environmental day/night changes through extra-SCN pathways.…”

Section: Introductionmentioning

confidence: 93%

The role of feeding rhythm, adrenal hormones and neuronal inputs in synchronizing daily clock gene rhythms in the liver

Cailotto

Foppen

et al. 2016

Molecular and Cellular Endocrinology

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Real-time recording of circadian liver gene expression in freely moving mice reveals the phase-setting behavior of hepatocyte clocks

Cited by 135 publications

References 50 publications

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

Liver Perilipin 5 Expression Worsens Hepatosteatosis But Not Insulin Resistance in High Fat-Fed Mice

The role of feeding rhythm, adrenal hormones and neuronal inputs in synchronizing daily clock gene rhythms in the liver

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