CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1

Zhou, Ben; Zhang, Yi; Zhang, Fang; Xia, Yulei; Li, Jun; Huang, Rui; Wang, Yuangao; Hu, Yanan; Wu, Jingxia; Dai, Changgui; Wang, Hui; Tu, Yanyang; Peng, Xiaozhong; Wang, Yiqian; Zhai, Qiwei

doi:10.1002/hep.26992

Cited by 118 publications

(101 citation statements)

References 51 publications

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“…However, palmitate treatment renders BMAL1 protein level constant throughout the cycle without showing effects on CLOCK. Meanwhile, chronic palmitate treatment modestly elevates p38 phosphorylation but greatly dampens AKT phosphorylation in those cells, consistent with recent findings that impairment of the hepatic circadian clock reduces AKT phosphorylation [56, 57]. Our results indicate that palmitate represses the hepatic molecular clock without reducing the overall protein abundance of nuclear BMAL1 and CLOCK in hepatocytes.…”

Section: Resultssupporting

confidence: 91%

Palmitate Inhibits SIRT1-Dependent BMAL1/CLOCK Interaction and Disrupts Circadian Gene Oscillations in Hepatocytes

et al. 2015

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Elevated levels of serum saturated fatty acid palmitate have been shown to promote insulin resistance, increase cellular ROS production, and trigger cell apoptosis in hepatocytes during the development of obesity. However, it remains unclear whether palmitate directly impacts the circadian clock in hepatocytes, which coordinates nutritional inputs and hormonal signaling with downstream metabolic outputs. Here we presented evidence that the molecular clock is a novel target of palmitate in hepatocytes. Palmitate exposure at low dose inhibits the molecular clock activity and suppresses the cyclic expression of circadian targets including Dbp, Nr1d1 and Per2 in hepatocytes. Palmitate treatment does not seem to alter localization or reduce protein expression of BMAL1 and CLOCK, the two core components of the molecular clock in hepatocytes. Instead, palmitate destabilizes the protein-protein interaction between BMAL1-CLOCK in a dose and time-dependent manner. Furthermore, we showed that SIRT1 activators could reverse the inhibitory action of palmitate on BMAL1-CLOCK interaction and the clock gene expression, whereas inhibitors of NAD synthesis mimic the palmitate effects on the clock function. In summary, our findings demonstrated that palmitate inhibits the clock function by suppressing SIRT1 function in hepatocytes.

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Section: Resultssupporting

confidence: 91%

Palmitate Inhibits SIRT1-Dependent BMAL1/CLOCK Interaction and Disrupts Circadian Gene Oscillations in Hepatocytes

et al. 2015

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“…Our data validate that whole body insulin tolerance in mice follows a diurnal pattern with lowest response to insulin during the early light phase. Similar results have previously been reported (Shi et al, 2013; Zhou et al, 2014). Insulin signaling and sensitivity in isolated skeletal muscle peaked during the dark phase.…”

Section: Discussionsupporting

confidence: 93%

“…The importance of the liver for the circadian changes in insulin tolerance has been demonstrated by use of liver-specific Bmal1 knockout mice. These mice have reduced insulin tolerance and lost circadian rhythmicity in insulin tolerance (Lamia et al, 2008; Zhou et al, 2014). Circadian changes in liver insulin sensitivity can partly explain the discrepancy between whole-body glucose disposal during the ITT and the insulin-stimulated glucose uptake measured in vivo in skeletal muscle and adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

Skeletal Muscle Insulin Sensitivity Show Circadian Rhythmicity Which Is Independent of Exercise Training Status

et al. 2018

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Circadian rhythms can be perturbed by shift work, travel across time zones, many occupational tasks, or genetic mutations. Perturbed circadian rhythms are associated with the increasing problem of obesity, metabolic dysfunction, and insulin resistance. We hypothesized that insulin sensitivity in skeletal muscle follows a circadian pattern and that this pattern is important for overall metabolic function. This hypothesis was verified using mice as a model system. We observed circadian rhythmicity in whole body insulin tolerance, as well as in signaling pathways regulating insulin- and exercise-induced glucose uptake in skeletal muscle, including AKT, 5′-adenosine monophosphate-activated protein kinase (AMPK) and TBC1 domain family member 4 (TBC1D4) phosphorylation. Basal and insulin-stimulated glucose uptake in skeletal muscle and adipose tissues in vivo also differed between day- and nighttime. However, the rhythmicity of glucose uptake differed from the rhythm of whole-body insulin tolerance. These results indicate that neither skeletal muscle nor adipose tissue play a major role for the circadian rhythmicity in whole-body insulin tolerance. To study the circadian pattern of insulin sensitivity directly in skeletal muscle, we determined glucose uptake under basal and submaximal insulin-stimulated conditions ex vivo every sixth hour. Both insulin sensitivity and signaling of isolated skeletal muscle peaked during the dark period. We next examined the effect of exercise training on the circadian rhythmicity of insulin sensitivity. As expected, voluntary exercise training enhanced glucose uptake in skeletal muscle. Nevertheless, exercise training did not affect the circadian rhythmicity of skeletal muscle insulin sensitivity. Taken together, our results provide evidence that skeletal muscle insulin sensitivity exhibits circadian rhythmicity.

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“…Overall, CS-mediated reduction of SIRT1 level and activity may contribute to clock dysfunction and proinflammatory cytokine release in patients with COPD. Recent studies have shown that CLOCK: BMAL1 enhancer complexes bind to the SIRT1 promoter to enhance its expression in liver and that SIRT1 gene expression is reduced in skeletal muscle of REV-ERBa knockout mice (43,44). However, the levels of SIRT1 were not changed in lungs of Bmal1 or Rev-erba knockout mice as compared with wild-type mice (unpublished data).…”

Section: Original Researchmentioning

confidence: 89%

Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

Yao¹,

Sundar²,

Huang³

et al. 2015

Am J Respir Cell Mol Biol

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Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death, and it is characterized by abnormal inflammation and lung function decline. Although the circadian molecular clock regulates inflammatory responses, there is no information available regarding the impact of COPD on lung molecular clock function and its regulation by sirtuin 1 (SIRT1). We hypothesize that the molecular clock in the lungs is disrupted, leading to increased inflammatory responses in smokers and patients with COPD and its regulation by SIRT1. Lung tissues, peripheral blood mononuclear cells (PBMCs), and sputum cells were obtained from nonsmokers, smokers, and patients with COPD for measurement of core molecular clock proteins (BMAL1, CLOCK, PER1, PER2, and CRY1), clock-associated nuclear receptors (REV-ERBa, REV-ERBb, and RORa), and SIRT1 by immunohistochemistry, immunofluorescence, and immunoblot. PBMCs were treated with the SIRT1 activator SRT1720 followed by LPS treatment, and supernatant was collected at 6-hour intervals. Levels of IL-8, IL-6, and TNF-a released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBa was reduced in PBMCs, sputum cells, and lung tissues from smokers and patients with COPD when compared with nonsmokers. SRT1720 treatment attenuated LPS-mediated reduction of BMAL1 and REV-ERBa in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-a) release from PBMCs in nonsmokers, smokers, and patients with COPD. Moreover, SRT1720 was able to inhibit LPS-induced cytokine release from cultured PBMCs. In conclusion, disruption of the molecular clock due to SIRT1 reduction contributes to abnormal inflammatory response in smokers and patients with COPD.Keywords: circadian rhythm; SIRT1; REV-ERBa; BMAL1; smokers Clinical RelevanceAlthough the circadian clock regulates the inflammatory response, there is no information available regarding the impact of chronic obstructive pulmonary disease (COPD) on molecular clock function in peripheral tissues and its modulation by sirtuin 1 (SIRT1). We report here that clock proteins, including BMAL1 and REV-ERBa, are reduced in peripheral tissues from patients with COPD in part owing to SIRT1 reduction. LPS differently affects the timing and amplitude of cytokine release from peripheral blood mononuclear cells among nonsmokers, smokers, and patients with COPD. The SIRT1 activator SRT1720 is able to inhibit LPS-induced cytokine release in peripheral blood mononuclear cells. This has implications in the pathogenesis and pharmacological chronotherapy of COPD.

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CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1

Cited by 118 publications

References 51 publications

Palmitate Inhibits SIRT1-Dependent BMAL1/CLOCK Interaction and Disrupts Circadian Gene Oscillations in Hepatocytes

Palmitate Inhibits SIRT1-Dependent BMAL1/CLOCK Interaction and Disrupts Circadian Gene Oscillations in Hepatocytes

Skeletal Muscle Insulin Sensitivity Show Circadian Rhythmicity Which Is Independent of Exercise Training Status

Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

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