The importance of being rhythmic: Living in harmony with your body clocks

Dibner, Charna

doi:10.1111/apha.13281

Cited by 35 publications

(34 citation statements)

References 214 publications

(496 reference statements)

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“…The mammalian circadian system consists of a master clock in the hypothalamic suprachiasmatic nuclei and subordinate peripheral oscillators in other brain regions and peripheral tissues, including the liver and adipose tissue [ 7 , 8 ]. This internal timekeeping system generates and orchestrates circadian rhythms in daily physiology and behavior from the molecular level to the whole-body level in order to anticipate and coordinate periodic environmental changes and metabolic requirements [ 9 ]. The oscillations of the master clock are entrained by the main external time-giver, the 24-h light-dark (LD) cycle, and the processed signal is then transmitted via neuronal, hormonal, and behavioral pathways to the periphery [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Dim Light at Night Disturbs Molecular Pathways of Lipid Metabolism

Okuliarova

Rumanova

Stebelová

et al. 2020

IJMS

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Dim light at night (dLAN) is associated with metabolic risk but the specific effects on lipid metabolism have only been evaluated to a limited extent. Therefore, to explore whether dLAN can compromise lipid metabolic homeostasis in healthy individuals, we exposed Wistar rats to dLAN (~2 lx) for 2 and 5 weeks and analyzed the main lipogenic pathways in the liver and epididymal fat pad, including the control mechanisms at the hormonal and molecular level. We found that dLAN promoted hepatic triacylglycerol accumulation, upregulated hepatic genes involved in de novo synthesis of fatty acids, and elevated glucose and fatty acid uptake. These observations were paralleled with suppressed fatty acid synthesis in the adipose tissue and altered plasma adipokine levels, indicating disturbed adipocyte metabolic function with a potential negative impact on liver metabolism. Moreover, dLAN-exposed rats displayed an elevated expression of two peroxisome proliferator-activated receptor family members (Pparα and Pparγ) in the liver and adipose tissue, suggesting the deregulation of important metabolic transcription factors. Together, our results demonstrate that an impaired balance of lipid biosynthetic pathways caused by dLAN can increase lipid storage in the liver, thereby accounting for a potential linking mechanism between dLAN and metabolic diseases.

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Section: Introductionmentioning

confidence: 99%

Dim Light at Night Disturbs Molecular Pathways of Lipid Metabolism

Okuliarova

Rumanova

Stebelová

et al. 2020

IJMS

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“…In mammals, this time-keeping system governs most aspects of physiology and behavior. It comprises a master pacemaker, located in the paired suprachiasmatic nuclei (SCN) of the hypothalamus, that on a daily basis synchronizes peripheral oscillators situated in the organs (1). The circadian system orchestrates body metabolism via diverse neural and humoral pathways, thus ensuring the finetuning of the metabolic processes to the rest-activity and feeding-fasting cycles.…”

mentioning

confidence: 99%

In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis

Petrenko

Gandasi

Sage

et al. 2020

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

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Circadian clocks operative in pancreatic islets participate in the regulation of insulin secretion in humans and, if compromised, in the development of type 2 diabetes (T2D) in rodents. Here we demonstrate that human islet α- and β-cells that bear attenuated clocks exhibit strongly disrupted insulin and glucagon granule docking and exocytosis. To examine whether compromised clocks play a role in the pathogenesis of T2D in humans, we quantified parameters of molecular clocks operative in human T2D islets at population, single islet, and single islet cell levels. Strikingly, our experiments reveal that islets from T2D patients contain clocks with diminished circadian amplitudes and reduced in vitro synchronization capacity compared to their nondiabetic counterparts. Moreover, our data suggest that islet clocks orchestrate temporal profiles of insulin and glucagon secretion in a physiological context. This regulation was disrupted in T2D subjects, implying a role for the islet cell-autonomous clocks in T2D progression. Finally, Nobiletin, an agonist of the core-clock proteins RORα/γ, boosted both circadian amplitude of T2D islet clocks and insulin secretion by these islets. Our study emphasizes a link between the circadian clockwork and T2D and proposes that clock modulators hold promise as putative therapeutic agents for this frequent disorder.

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“…All photosensitive organisms possess circadian clocks synchronizing the temporal organization of cell and system physiology with the rotation of the earth [1][2][3][4][5][6][7]. The master pacemaker of the mammalian circadian clock is the suprachiasmatic nucleus (SCN) of the hypothalamus, which is mainly timed by light input [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases and Immunoproteasomal Activity

Andersen¹,

Petrenko²,

Rose³

et al. 2020

Preprint

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Pancreatic β-cell-specific clock knock-out mice develop β cell oxidative-stress and failure, as well as glucose-intolerance. How inflammatory stress affects the cellular clock is under-investigated. Real-time recording of Per2:luciferase reporter activity in murine and human pancreatic islets demonstrated that the proinflammatory cytokine Interleukin-1β (IL-1β) lengthened the circadian period. qPCR-profiling of core clock gene expression in insulin-producing cells suggested that the combination of the proinflammatory cytokines IL-1β and Interferon-γ (IFN-γ) caused pronounced but uncoordinated increases in mRNA levels of multiple core clock genes, in particular of Reverse-erythroblastosis virus α (Rev-erbα), in a dose- and time-dependent manner. The REV-ERBα/β agonist SR9009, used to mimic cytokine-mediated Rev-erbα induction, reduced constitutive and cytokine-induced Brain and muscle arnt-like 1 (Bmal1) mRNA levels in INS-1 cells as expected. SR9009 induced reactive oxygen species (ROS), reduced insulin-1/2 (Ins-1/2) mRNA and accumulated- and glucose-stimulated insulin secretion, reduced cell-viability, and increased apoptosis levels, reminiscent of cytokine toxicity. In contrast low (<5,0 μM) concentrations of SR9009 increased Ins-1 mRNA and accumulated insulin-secretion without affecting INS-1 cell viability, mirroring low-concentration IL-1β mediated β-cell stimulation. Inhibiting nitric oxide (NO) synthesis, the lysine deacetylase HDAC3 and the immunoproteasome reduced cytokine-mediated increases in clock gene expression. In conclusion, the cytokine-combination perturbed the intrinsic clocks operative in mouse and human pancreatic islets and induced uncoordinated clock gene expression in INS-1 cells, the latter effect associated with NO, HDAC3 and immunoproteasome activity.

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The importance of being rhythmic: Living in harmony with your body clocks

Cited by 35 publications

References 214 publications

Dim Light at Night Disturbs Molecular Pathways of Lipid Metabolism

Dim Light at Night Disturbs Molecular Pathways of Lipid Metabolism

In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis

Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases and Immunoproteasomal Activity

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