Bmal1 deletion in mice facilitates adaptation to disrupted light/dark conditions

Yang, Guangrui; Zhang, Jiayang; Ren, Baoyin; FitzGerald, Garret A.

doi:10.1172/jci.insight.125133

Cited by 16 publications

(19 citation statements)

References 18 publications

(19 reference statements)

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“…Reduced substrates utilization was observed in Bmal1 KO skeletal muscle ( 30 , 63 ). A recent study showed that Bmal1 deletion also protects mice from insulin resistance induced by circadian disruption ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the Circadian Clock Gene Bmal1 Reduces Microglial Immunometabolism

et al. 2020

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Microglia are brain immune cells responsible for immune surveillance. Microglial activation is, however, closely associated with neuroinflammation, neurodegeneration, and obesity. Therefore, it is critical that microglial immune response appropriately adapts to different stressors. The circadian clock controls the cellular process that involves the regulation of inflammation and energy hemostasis. Here, we observed a significant circadian variation in the expression of markers related to inflammation, nutrient utilization, and antioxidation in microglial cells isolated from mice. Furthermore, we found that the core clock gene-Brain and Muscle Arnt-like 1 (Bmal1) plays a role in regulating microglial immune function in mice and microglial BV-2 cells by using quantitative RT-PCR. Bmal1 deficiency decreased gene expression of pro-inflammatory cytokines, increased gene expression of antioxidative and anti-inflammatory factors in microglia. These changes were also observed in Bmal1 knock-down microglial BV-2 cells under lipopolysaccharide (LPS) and palmitic acid stimulations. Moreover, Bmal1 deficiency affected the expression of metabolic associated genes and metabolic processes, and increased phagocytic capacity in microglia. These findings suggest that Bmal1 is a key regulator in microglial immune response and cellular metabolism.

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Section: Discussionmentioning

confidence: 99%

Deficiency of the Circadian Clock Gene Bmal1 Reduces Microglial Immunometabolism

et al. 2020

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“…Despite an increasing awareness of the hazards of circadian disruption, modern lifestyle is subject to frequent desynchronization due to shift working, artificial light, and transmeridian air flight. While the molecular clock may be adjusted by small molecules that target clock proteins ( Cho et al, 2012 ; Solt et al, 2012 ; Wallach and Kramer, 2015 ), we have found that inhibiting circadian rhythms may also mitigate circadian disorders ( Yang et al, 2019 , 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Impact of Time-Restricted Feeding to Late Night on Adaptation to a 6 h Phase Advance of the Light-Dark Cycle in Mice

Ren

FitzGerald

et al. 2021

Front. Physiol.

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In modern society, more and more people suffer from circadian disruption, which in turn affects health. But until now, there are no widely accepted therapies for circadian disorders. Rhythmic feeding behavior is one of the most potent non-photic zeitgebers, thus it has been suggested that it was important to eat during specific periods of time (time-restricted feeding, TRF) so that feeding is aligned with environmental cues under normal light/dark conditions. Here, we challenged mice with a 6 h advanced shift, combined with various approaches to TRF, and found that food restricted to the second half of the nights after the shift facilitated adaptation. This coincided with improved resilience to sepsis. These results raise the possibility of reducing the adverse responses to jet lag by subsequent timing of food intake.

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“…This is consistent with the finding of loss of circadian behavior in iKO mice, however, it may not necessarily mean that the renal function was impaired. 7,31 Moreover, we observed a trend toward augmented excretion of water and electrolytes in the urine of the iKO mice when mice were inactive during the daytime period, while the food and water intake were also simultaneously increased, implying that the altered urine parameters in the iKO mice may largely reflect the intake behavioral changes. Similar to the abolished circadian profiles of waterelectrolyte excretion, the typical day-night variation of arterial blood pressure was blunted in the iKO mice, which is mainly due to an absence of the blood pressure rise during the active phase, this is consistent to our previous report.…”

Section: Discussionmentioning

confidence: 77%

“…At the heart of the complex regulatory network is the heterodimeric partnership between BMAL1 and CLOCK, which drive the oscillatory gene expression by binding to E‐box elements (CANNTG) in promoter regions of target genes 5 . Particularly, Bmal1 is the only core clock gene whose sole deletion, either prenatal or postnatal global knockout, results in complete loss of circadian rhythms in both behavior and some physiological functions such as blood pressure and heart rate 6‐8 …”

Section: Introductionmentioning

confidence: 99%

“…5 Particularly, Bmal1 is the only core clock gene whose sole deletion, either prenatal or postnatal global knockout, results in complete loss of circadian rhythms in both behavior and some physiological functions such as blood pressure and heart rate. [6][7][8] Kidney was second only to the liver in terms of the number of oscillating genes. 9 Concomitantly, many renal physiological functions, such as renal plasma flow, the glomerular filtration rate (GFR), water and electrolyte excretion, and renal control of blood pressure, are all exhibiting circadian oscillations.…”

Section: Introductionmentioning

confidence: 99%

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Postnatal deletion of Bmal1 in mice protects against obstructive renal fibrosis via suppressing Gli2 transcription

et al. 2021

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Circadian clock is involved in regulating most renal physiological functions, including water and electrolyte balance and blood pressure homeostasis, however, the role of circadian clock in renal pathophysiology remains largely unknown. Here we aimed to investigate the role of Bmal1, a core clock component, in the development of renal fibrosis, the hallmark of pathological features in many renal diseases. The inducible Bmal1 knockout mice (iKO) whose gene deletion occurred in adulthood were used in the study. Analysis of the urinary water, sodium and potassium excretion showed that the iKO mice exhibit abolished diurnal variations. In the model of renal fibrosis induced by unilateral ureteral obstruction, the iKO mice displayed significantly decreased tubulointerstitial fibrosis reflected by attenuated collagen deposition and mitigated expression of fibrotic markers α-SMA and fibronectin. The hedgehog pathway transcriptional effectors Gli1 and Gli2, which have been reported to be involved in the pathogenesis of renal fibrosis, were significantly decreased in the iKO mice. Mechanistically, ChIP assay and luciferase reporter assay revealed that BMAL1 bound to the promoter of and activate the transcription of Gli2, but not Gli1, suggesting that the involvement of Bmal1 in renal fibrosis was possibly mediated via Gli2-dependent mechanisms. Furthermore, treatment with TGF-β increased Bmal1 in cultured murine proximal tubular cells. Knockdown of Bmal1 abolished, while overexpression of Bmal1 increased, Gli2 and the expression of fibrosis-related genes. Collectively, these results revealed a prominent role of the core clock gene Bmal1 in tubulointerstitial fibrosis. Moreover, we identified Gli2 as a novel target of Bmal1, which may mediate the adverse effect of Bmal1 in obstructive nephropathy.

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Bmal1 deletion in mice facilitates adaptation to disrupted light/dark conditions

Cited by 16 publications

References 18 publications

Deficiency of the Circadian Clock Gene Bmal1 Reduces Microglial Immunometabolism

Deficiency of the Circadian Clock Gene Bmal1 Reduces Microglial Immunometabolism

Impact of Time-Restricted Feeding to Late Night on Adaptation to a 6 h Phase Advance of the Light-Dark Cycle in Mice

Postnatal deletion of Bmal1 in mice protects against obstructive renal fibrosis via suppressing Gli2 transcription

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