Circadiane Uhren und Energiemetabolismus

Chrononutrition – circadian clocks and energy metabolism Genetically encoded endogenous clocks regulate 24‐hour rhythms of physiology and behavior. A central pacemaker residing in the suprachiasmatic nucleus synchronizes peripheral clocks found in all tissues with each other and with the external day‐night cycle. One function of circadian clocks is the regulation of energy metabolism via rhythmic activation of tissue‐specific clock‐controlled genes. In the liver, genes involved in glucose and lipid metabolism are regulated in this fashion, while in adipocytes, fatty acid release and adipokine secretion are controlled by the circadian clock. Disruption of circadian rhythms as seen, for example, in shift workers promotes the development of metabolic disorders such as obesity and type‐2 diabetes.     

Development of Circadian Oscillators in Neurosphere Cultures during Adult Neurogenesis

Circadian rhythms are common in many cell types but are reported to be lacking in embryonic stem cells. Recent studies have described possible interactions between the molecular mechanism of circadian clocks and the signaling pathways that regulate stem cell differentiation. Circadian rhythms have not been examined well in neural stem cells and progenitor cells that produce new neurons and glial cells during adult neurogenesis. To evaluate circadian timing abilities of cells undergoing neural differentiation, neurospheres were prepared from the mouse subventricular zone (SVZ), a rich source of adult neural stem cells. Circadian rhythms in mPer1 gene expression were recorded in individual spheres, and cell types were characterized by confocal immunofluorescence microscopy at early and late developmental stages in vitro. Circadian rhythms were observed in neurospheres induced to differentiate into neurons or glia, and rhythms emerged within 3–4 days as differentiation proceeded, suggesting that the neural stem cell state suppresses the functioning of the circadian clock. Evidence was also provided that neural stem progenitor cells derived from the SVZ of adult mice are self-sufficient clock cells capable of producing a circadian rhythm without input from known circadian pacemakers of the organism. Expression of mPer1 occurred in high frequency oscillations before circadian rhythms were detected, which may represent a role for this circadian clock gene in the fast cycling of gene expression responsible for early cell differentiation.     

A neural clockwork for encoding circadian time.

Many daily biological rhythms are governed by an innate timekeeping mechanism or clock. Endogenous, temperature-compensated circadian clocks have been localized to discrete sites within the nervous systems of a number of organisms. In mammals, the master circadian pacemaker is the bilaterally paired suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The SCN is composed of multiple single cell oscillators that must synchronize to each other and the environmental light schedule. Other tissues, including those outside the nervous system, have also been shown to express autonomous circadian periodicities. This review examines 1) how intracellular regulatory molecules function in the oscillatory mechanism and in its entrainment to environmental cycles; 2) how individual SCN cells interact to create an integrated tissue pacemaker with coherent metabolic, electrical, and secretory rhythms; and 3) how such clock outputs are converted into temporal programs for the whole organism.     

Are Circadian Rhythms the Code of Hypothalamic-Immune Communication? Insights from Natural Killer Cells

Circadian rhythms in physiology and behavior are ultimately regulated at the hypothalamic level by the suprachiasmatic nuclei (SCN). This central oscillator transduces photic information to the cellular clocks in the periphery through the autonomic nervous system and the neuroendocrine system. The fact that these two systems have been shown to modulate leukocyte physiology supports the concept that the circadian component is an important aspect of hypothalamic-immune communication. Circadian disruption has been linked to immune dysregulation, and recent reports suggest that several circadian clock genes, in addition to their time-keeping role, are involved in the immune response. In this overview, we summarize the findings demonstrating that Natural Killer (NK) cell function is under circadian control. Special issue article in honor of George Fink.     

Sirt1与生物钟的相互调控

生物钟调控机制广泛存在于各种类型的细胞中,控制着细胞代谢的节律性变化.最近的研究发现,NAD+依赖的组蛋白去乙酰化酶Sirt1参与了生物钟调控过程,对维持正常的生物钟节律具有重要作用;另一方面,Sirt1的表达也受到生物钟系统的调控,呈现出昼夜节律性的表达.因此Sirt1能与生物钟进行相互调控,并且这一作用机制很可能广泛参与了不同类型细胞内的信号转导和能量代谢过程.本文总结了Sirt1与生物钟之间相互调控的一些研究进展,对它们之间的分子调控机制进行了概述.     

The clock input to the first optic neuropil of Drosophila melanogaster expressing neuronal circadian plasticity

In the first optic neuropil (lamina) of the fly's visual system, two interneurons, L1 and L2 monopolar cells, and epithelial glial cells show circadian rhythms in morphological plasticity. These rhythms depend on clock gene period (per) and cryptochrome (cry) expression. In the present study, we found that rhythms in the lamina of Drosophila melanogaster may be regulated by circadian clock neurons in the brain since the lamina is invaded by one neurite extending from ventral lateral neurons; the so-called pacemaker neurons. These neurons and the projection to the lamina were visualized by green fluorescent protein (GFP). GFP reporter gene expression was driven by the cry promotor in cry-GAL4/UAS-GFP transgenic lines. We observed that the neuron projecting to the lamina forms arborizations of varicose fibers in the distal lamina. These varicose fibers do not form synaptic contacts with the lamina cells and are immunoreactive to the antisera raised against a specific region of Schistocerca gregaria ion transport peptide (ITP). ITP released in a paracrine way in the lamina cortex, may regulate the swelling and shrinking rhythms of the lamina monopolar cells and the glia by controlling the transport of ions and fluids across cell membranes at particular times of the day.     

生物节律影响巨核细胞发育和血小板产生的研究进展

自然界中生物体的生命活动、生活习性都存在着一定的周期性变化。生物昼夜节律的产生是以内源性的生物钟系统为基础的。生物钟不仅易受到外界环境的影响,而且可以通过调控一系列特定的下游基因的表达,影响生物体的生理生化过程。巨核细胞是生成血小板的前体细胞,经过分化、增殖、成熟和裂解,最终生成血小板。血小板是一种没有细胞核的特殊细胞,在生理性止血和器官修复上发挥着重要作用,同时参与血栓等多种疾病的发生。近几年借助现代分子生物学和细胞生物学手段。证实了哺乳动物的巨核细胞和血小板的生成呈现明显的周期性的变化,利用生物钟基因缺失模型进一步发现了生物钟基因对巨核细胞和血小板的影响。本文概述了生物节律对巨核细胞和血小板的影响,为进一步研究巨核细胞的发育和血小板生成机制提供了参考。     

The nature of the root clock at single cell resolution: Principles of communication and similarities with plant and animal pulsatile and circadian mechanisms

Oscillatory mechanisms are present in most life forms and regulate biological processes periodically. In multicellular organisms where more than one oscillatory mechanism is present, they are organized forming a hierarchical coordinated system even at the cellular level. Here, we focus on the Root Clock, an oscillatory mechanism located at the tip of roots that patterns the spacing of lateral organs through oscillating gene expression. We present a series of recent findings and hypotheses about the cellular mechanisms driving the oscillations, how oscillatory information is transmitted within this clock and similarities with other oscillatory systems. Next, we review principles of communication in other pulsatile mechanisms such as circadian rhythms in plants and mammals, and address the possible communication between plant circadian rhythms and the Root Clock. Finally, we advocate for the use of single-cell approaches to address cell communication, synchronization and integration of external outputs into the Root Clock system.     

Putative circadian pacemaker cells in the antenna of the hawkmoth Manduca sexta

Antennal sensory neurons in the fruit fly Drosophila melanogaster express circadian rhythms in the clock gene PERIOD (PER) and appear to be sufficient and necessary for circadian rhythms in olfactory responses. Given recent evidence for daily rhythms of pheromone responses in the antenna of the hawkmoth Manduca sexta, we examined whether a peripheral PER-based circadian clock might be present in this species. Several different cell types in the moth antenna were recognized by monoclonal antibodies against Manduca sexta PER. In addition to PER-like staining of pheromone-sensitive olfactory receptor neurons and supporting cells, immunoreactivity was detected in beaded branches contacting the pheromone-sensitive sensilla. The nuclei of apparently all sensory receptor neurons, of sensilla supporting cells, of epithelial cells, and of antennal nerve glial cells were PER-immunoreactive. Expression of per mRNA in antennae was confirmed by the polymerase chain reaction, which showed stronger expression at Zeitgeber-time 15 compared with Zeitgeber-time 3. This evidence for the expression of per gene products suggests that the antenna of the hawkmoth contains endogenous circadian clocks.     

Influence of the estrous cycle on clock gene expression in reproductive tissues: Effects of fluctuating ovarian steroid hormone levels

Circadian rhythms in physiology and behavior are known to be influenced by the estrous cycle in female rodents. The clock genes responsible for the generation of circadian oscillations are widely expressed both within the central nervous system and peripheral tissues, including those that comprise the reproductive system. To address whether the estrous cycle affects rhythms of clock gene expression in peripheral tissues, we first examined rhythms of clock gene expression (Per1, Per2, Bmal1) in reproductive (uterus, ovary) and non-reproductive (liver) tissues of cycling rats using quantitative real-time PCR (in vivo) and luminescent recording methods to measure circadian rhythms of PER2 expression in tissue explant cultures from cycling PER2::LUCIFERASE (PER2::LUC) knockin mice (ex vivo). We found significant estrous variations of clock gene expression in all three tissues in vivo, and in the uterus ex vivo. We also found that exogenous application of estrogen and progesterone altered rhythms of PER2::LUC expression in the uterus. In addition, we measured the effects of ovarian steroids on clock gene expression in a human breast cancer cell line (MCF-7 cells) as a model for endocrine cells that contain both the steroid hormone receptors and clock genes. We found that progesterone, but not estrogen, acutely up-regulated Per1, Per2, and Bmal1 expression in MCF-7 cells. Together, our findings demonstrate that the timing of the circadian clock in reproductive tissues is influenced by the estrous cycle and suggest that fluctuating steroid hormone levels may be responsible, in part, through direct effects on the timing of clock gene expression.     

When clocks go bad: neurobehavioural consequences of disrupted circadian timing

Progress in unravelling the cellular and molecular basis of mammalian circadian regulation over the past decade has provided us with new avenues through which we can explore central nervous system disease. Deteriorations in measurable circadian output parameters, such as sleep/wake deficits and dysregulation of circulating hormone levels, are common features of most central nervous system disorders. At the core of the mammalian circadian system is a complex of molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by afferent signals from the environment, and integrated signals are subsequently conveyed to remote central neural circuits where specific output rhythms are regulated. Mutations in circadian genes in mice can disturb both molecular oscillations and measurable output rhythms. Moreover, systematic analysis of these mutants indicates that they can express an array of abnormal behavioural phenotypes that are intermediate signatures of central nervous system disorders. Furthermore, the response of these mutants to psychoactive drugs suggests that clock genes can modify a number of the brain’s critical neurotransmitter systems. This evidence has led to promising investigations into clock gene polymorphisms in psychiatric disease. Preliminary indications favour the systematic investigation of the contribution of circadian genes to central nervous system disease.     

Evidence for the adaptive significance of circadian rhythms

Circadian (∼24 h) clock regulated biological rhythms have been identified in a wide range of organisms from prokaryotic unicellular cyanobacteria to higher mammals. These rhythms regulate an enormous variety of processes including gene expression, metabolic processes, activity and reproduction. Given the widespread occurrence of circadian systems it is not surprising that extensive efforts have been directed at understanding the adaptive significance of circadian rhythms. In this review we discuss the approaches and findings that have resulted. In studies on organisms in their natural environments, some species show adaptations in their circadian systems that correlate with living at different latitudes, such as clines in circadian clock properties. Additionally, some species show plasticity in their circadian systems suggested to match the demands of their physical and social environment. A number of experiments, both in the field and in the laboratory, have examined the effects of having a circadian system that does not resonate with the organism's environment. We conclude that the results of these studies suggest that having a circadian system that matches the oscillating environment is adaptive.     

Thematic Review Series: Intestinal Lipid Metabolism: New Developments and Current Insights: Circadian regulators of intestinal lipid absorption

Among all the metabolites present in the plasma, lipids, mainly triacylglycerol and diacylglycerol, show extensive circadian rhythms. These lipids are transported in the plasma as part of lipoproteins. Lipoproteins are synthesized primarily in the liver and intestine and their production exhibits circadian rhythmicity. Studies have shown that various proteins involved in lipid absorption and lipoprotein biosynthesis show circadian expression. Further, intestinal epithelial cells express circadian clock genes and these genes might control circadian expression of different proteins involved in intestinal lipid absorption. Intestinal circadian clock genes are synchronized by signals emanating from the suprachiasmatic nuclei that constitute a master clock and from signals coming from other environmental factors, such as food availability. Disruptions in central clock, as happens due to disruptions in the sleep/wake cycle, affect intestinal function. Similarly, irregularities in temporal food intake affect intestinal function. These changes predispose individuals to various metabolic disorders, such as metabolic syndrome, obesity, diabetes, and atherosclerosis. Here, we summarize how circadian rhythms regulate microsomal triglyceride transfer protein, apoAIV, and nocturnin to affect diurnal regulation of lipid absorption.     

Glial cells

The nervous system is built from two broad categories of cells, neurones and glial cells. The glial cells outnumber the neurones and the two cell types occupy a comparable amount of space in nervous tissue. The main glial cell types are, in the central nervous system, astrocytes and oligodendrocytes and, in the peripheral nervous system, Schwann cells, enteric glial cells and satellite cells. In the embryo, glial cells form a cellular framework that permits the development of the rest of the nervous system, and regulate neuronal survival and differentiation. The best known function of glia in the adult is the formation of myelin sheaths around axons thus allowing the fast conduction of signalling essential for nervous system function. Glia also maintain appropriate concentrations of ions and neurotransmitters in the neuronal environment. Increasing body of evidence indicates that glial cells are essential regulators of the formation, maintenance and function of synapses, the key functional unit of the nervous system.     

Drosophila ebony activity is required in glia for the circadian regulation of locomotor activity

Previous studies suggest that glia may be required for normal circadian behavior, but glial factors required for rhythmicity have not been identified in any system. We show here that a circadian rhythm in Drosophila Ebony (N-beta-alanyl-biogenic amine synthetase) abundance can be visualized in adult glia and that glial expression of Ebony rescues the altered circadian behavior of ebony mutants. We demonstrate that molecular oscillator function and clock neuron output are normal in ebony mutants, verifying a role for Ebony downstream of the clock. Surprisingly, the ebony oscillation persists in flies lacking PDF neuropeptide, indicating it is regulated by an autonomous glial oscillator or another neuronal factor. The proximity of Ebony-containing glia to aminergic neurons and genetic interaction results suggest a function in dopaminergic signaling. We thus suggest a model for ebony function wherein Ebony glia participate in the clock control of dopaminergic function and the orchestration of circadian activity rhythms.