Diurnal Regulation of Lipid Metabolism and Applications of Circadian Lipidomics

The circadian timing system plays a key role in orchestrating lipid metabolism. In concert with the solar cycle, the circadian system ensures that daily rhythms in lipid absorption, storage, and transport are temporally coordinated with rest-activity and feeding cycles. At the cellular level, genes involved in lipid synthesis and fatty acid oxidation are rhythmically activated and repressed by core clock proteins in a tissue-specific manner. Consequently, loss of clock gene function or misalignment of circadian rhythms with feeding cycles （e.g., in shift work） results in impaired lipid homeostasis. Herein, we review recent progress in circadian rhythms research using lipidomics, i.e., large-scale profiling of lipid metabolites, to characterize circadian-regulated lipid pathways in mammals. In mice, novel regulatory circuits involved in fatty acid metabolism have been identified in adipose tissue, liver, and muscle. Extensive diversity in circadian regulation of plasma lipids has also been revealed in humans using lipidomics and other metabolomics approaches. In future studies, lipidomics platforms will be increasingly used to better understand the effects of genetic variation, shift work, food intake, and drugs on circadian-regulated lipid pathways and metabolic health.     

Circadian clock gene expression regulates cancer cell growth through glutaminase

Glutamine is an essential amino acid for malignant tumor cells. Glutaminase that metabolizes glutamine reaches a maximum expression in tumors immediately before the maximum proliferation rate. Tumor cells grow at different rates during the day. We postulated that the activity of glutaminase in tumor cells is subject to the regulation of circadian clock gene. We measured glutaminase by western blot analysis and circadian clock gene expression by real-time polymerase chain reaction in the liver and tumor cells at six equispaced time points of the day in individual mice of a 12/12 h light/dark schedule. The results showed that the tumor-bearing mice, under normal diurnal conditions, are circadianly entrained, as reflected by the normal host locomotor activity rhythms and rhythmic liver clock gene expression. The tumors within these mice are also circadianly organized, as reflected by circadian clock gene （Bmall） expression. What is most remarkable is that kidney-type glutaminase also showed circadian rhythms in the same pattern with tumor circadian clock gene expression in liver cancer xenograft model, indicating that conditionally inhibiting glutaminase activity may provide a new target for cancer therapy.     

Fitness consequences of altering floral circadian oscillations for Nicotiana attenuata

Ecological interactions between flowers and pollinators are all about timing.Flower opening/closing and scent emissions are largely synchronized with pollinator activity,and a circadian clock regulates these rhythms.However,whether the circadian clock increases a plant's reproductive success by regulating these floral rhythms remains untested.Flowers of Nicotiana attenuata,a wild tobacco,diurnally and rhythmically open,emit scent and move vertically through a 140° arc to interact with nocturnal hawkmoths.We tethered flowers to evaluate the importance of flower positions for Manduca sexta-mediated pollinations;flower position dramatically influenced pollination.We examined the pollination success of phase-shifted flowers,silenced in circadian clock genes,NaZTL,NaLHY,and NaTOCi,by RNAi.Circadian rhythms in N.attenuata flowers are responsible for altered seed set from outcrossed pollen.     

Deoxyribozymes inhibit the expression ofperiod1 genein vitro

Throughout biology, a broad range of biochemical and physiological processes oscillate with approxi-mately 24-h rhythms or circadian rhythms as synchro-nizing with the rhythmic environment (day/night cy-cles, seasons, etc.). The circadian rhythms are under the control of an endogenous oscillator, the circadian clock[1]. Period (per), the first genetically identified circadian mutant[2], is assumed to be a key molecule in the regulation and functioning of the mammalian cir-cadian clock which is…     

Melatonin in the seasonal response of the aphid Acyrthosiphon pisum

Aphids display life cycles largely determined by the photoperiod.During the warm long-day seasons.most aphid species reproduce by viviparous parthenogenesis.The shortening of the photoperiod in autumn induces a switch to sexual reproduction.Males and sexual females mate to produce overwintering resistant eggs.In addition to this full life cycle(holocycle),there are anholocyelic lineages that do not respond to changes in photoperiod and reproduce continuously by parthenogenesis.The molecular or hormonal events that trigger the scasonal response(i.c,induction of the sexual phenotypes)are still unknown.Although circadian synthesis of melatonin is known to play a key role in vertebrate photoperiodism,the involvement of the circadian clock and/or of the hor-mone melatonin in insect seasonal responses is not so well established.Here we show that melatonin levels in the aphid Acyrthosiphon pisum are significantly higher in holocyclice aphids reared under short days than under long days,while no differences were found between anholoeyelic aphids under the same conditions.We also found that melatonin is localized in the aphid suboesophageal ganglion(SOG)and in the thoracic ganglionic mass(TGM).In analogy to vertcbrates,insect-type arylalkxylamine N-acetyltransferases(i-AANATs)are thought to play a key role in melatonin synthesis.We measured the expression of four I-AANAT genes identified in A.pisum and localized two of them in situ in the insect central nervous systems(CNS).Levels of expression of these genes were compatible with the quantities of melatonin observed.Moreover,like melatonin,expression of these genes was found in the SOG and the TGM.     

Biological clock: the oscillator of gene expression

正The 2017 Nobel prize in physiology or medicine was awarded to the discoveries of genes and molecular mechanisms of the circadian rhythm,which is any biological process that oscillates with a period of about 24 h.Three scientists from the United States,Jeffrey C.Hall,Michael Rosbash,and Michael W.Young,shared the award.This work is of great theoretical value in understanding the nature of life and the interactions of life with its environments,and also has important application value in guiding the treatment     

植物防御系统中抗病相关基因的研究进展

本文论述了植物防御系统中抗病相关基因（resistance gene,R基因）的研究进展。列表总结了迄今已克隆的R基因,并将其归为四种不同的类型。综述了不同基因表达产物-R蛋白在细胞中的定位及其相应的功能。此外,还对R基因编码区的多态性、R基因在染色体上排列方式以及R基因的进化与起源等问题进行了讨论。 Abstract:This review comments on recent advances in research of disease resistance genes(R Genes) in defence system of plants.The R genes cloned up to date are summarized and classified roughly into four classes listed in the Table 1.The location and the founction of the R proteins,i.e.,the expressed products of different R genes in the cells are reviewed.In addition,the polymophism of coding region of R genes,the different fashions of R gene arrangement on the chromosomes,and the evolution and origin of R genes are discussed.     

MiR-29a/b/c regulate human circadian gene hPER1 expression by targeting its 3/UTR

Several essential biological progresses in mammals are regulated by circadian rhythms. Though the molecular mechanisms of oscillating these circadian rhythms have been uncovered, the specific functions of the circadian genes are not very clear. It has been reported that knocking down circadian genes by microRNA is a useful strategy to explore the function of the circadian rhythms. In this study, through a forward bioinformatics screening ap- proach, we identified miR-29a/b/c as potent inhibitors for the human circadian gene hPER1. We further found that miR-29a/b/c could directly target hPER1 3/untranslated region （UTR） and down-regulate hPER1 at both mRNA and protein expression levels in human A549 cells. Thus, our findings suggested that the expression of hPER1 is regulated by miR-29a/b/c, which may also provide a new clue for the function ofhPER1.     

Feeding Period Restriction Alters the Expression of Peripheral Circadian Rhythm Genes without Changing Body Weight in Mice

Accumulating evidence suggests that the circadian clock is closely associated with metabolic regulation. However, whether an impaired circadian clock is a direct cause of metabolic dysregulation such as body weight gain is not clearly understood. In this study, we demonstrate that body weight gain in mice is not significantly changed by restricting feeding period to daytime or nighttime. The expression of peripheral circadian clock genes was altered by feeding period restriction, while the expression of light-regulated hypothalamic circadian clock genes was unaffected by either a normal chow diet (NCD) or a high-fat diet (HFD). In the liver, the expression pattern of circadian clock genes, including Bmal1, Clock, and Per2, was changed by different feeding period restrictions. Moreover, the expression of lipogenic genes, gluconeogenic genes, and fatty acid oxidation-related genes in the liver was also altered by feeding period restriction. Given that feeding period restriction does not affect body weight gain with a NCD or HFD, it is likely that the amount of food consumed might be a crucial factor in determining body weight. Collectively, these data suggest that feeding period restriction modulates the expression of peripheral circadian clock genes, which is uncoupled from light-sensitive hypothalamic circadian clock genes.     

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 intrinsic circadian clock within the cardiomyocyte

Circadian clocks are intracellular molecular mechanisms that allow the cell to anticipate the time of day. We have previously reported that the intact rat heart expresses the major components of the circadian clock, of which its rhythmic expression in vivo is consistent with the operation of a fully functional clock mechanism. The present study exposes oscillations of circadian clock genes [brain and arylhydrocarbon receptor nuclear translocator-like protein 1 (bmal1), reverse strand of the c-erbaalpha gene (rev-erbaalpha), period 2 (per2), albumin D-element binding protein (dbp)] for isolated adult rat cardiomyocytes in culture. Acute (2 h) and/or chronic (continuous) treatment of cardiomyocytes with FCS (50% and 2.5%, respectively) results in rhythmic expression of circadian clock genes with periodicities of 20-24 h. In contrast, cardiomyocytes cultured in the absence of serum exhibit dramatically dampened oscillations in bmal1 and dbp only. Zeitgebers (timekeepers) are factors that influence the timing of the circadian clock. Glucose, which has been previously shown to reactivate circadian clock gene oscillations in fibroblasts, has no effect on the expression of circadian clock genes in adult rat cardiomyocytes, either in the absence or presence of serum. Exposure of adult rat cardiomyocytes to the sympathetic neurotransmitter norephinephrine (10 microM) for 2 h reinitiates rhythmic expression of circadian clock genes in a serum-independent manner. Oscillations in circadian clock genes were associated with 24-h oscillations in the metabolic genes pyruvate dehydrogenase kinase 4 (pdk4) and uncoupling protein 3 (ucp3). In conclusion, these data suggest that the circadian clock operates within the myocytes of the heart and that this molecular mechanism persists under standard cell culture conditions (i.e., 2.5% serum). Furthermore, our data suggest that norepinephrine, unlike glucose, influences the timing of the circadian clock within the heart and that the circadian clock may be a novel mechanism regulating myocardial metabolism.     

Deleting the Arntl clock gene in the granular layer of the mouse cerebellum: impact on the molecular circadian clockwork

The suprachiasmatic nucleus houses the central circadian clock and is characterized by the timely regulated expression of clock genes. However, neurons of the cerebellar cortex also contain a circadian oscillator with circadian expression of clock genes being controlled by the suprachiasmatic nucleus. It has been suggested that the cerebellar circadian oscillator is involved in food anticipation, but direct molecular evidence of the role of the circadian oscillator of the cerebellar cortex is currently unavailable. To investigate the hypothesis that the circadian oscillator of the cerebellum is involved in circadian physiology and food anticipation, we therefore by use of Cre‐LoxP technology generated a conditional knockout mouse with the core clock gene Arntl deleted specifically in granule cells of the cerebellum, since expression of clock genes in the cerebellar cortex is mainly located in this cell type. We here report that deletion of Arntl heavily influences the molecular clock of the cerebellar cortex with significantly altered and arrhythmic expression of other central clock and clock‐controlled genes. On the other hand, daily expression of clock genes in the suprachiasmatic nucleus was unaffected. Telemetric registrations in different light regimes did not detect significant differences in circadian rhythms of running activity and body temperature between Arntl conditional knockout mice and controls. Furthermore, food anticipatory behavior did not differ between genotypes. These data suggest that Arntl is an essential part of the cerebellar oscillator; however, the oscillator of the granular layer of the cerebellar cortex does not control traditional circadian parameters or food anticipation.     

MPer1 and mper2 are essential for normal resetting of the circadian clock

Mammalian Per1 and Per2 genes are involved in the mechanism of the circadian clock and are inducible by light. A light pulse can evoke a change in the onset of wheel-running activity in mice by shifting the onset of activity to earlier times (phase advance) or later times (phase delays) thereby advancing or delaying the clock (clock resetting). To assess the role of mouse Per (mPer) genes in circadian clock resetting, mice carrying mutant mPer1 or mPer2 genes were tested for responses to a light pulse at ZT 14 and ZT 22, respectively. The authors found that mPer1 mutants did not advance and mPer2 mutants did not delay the clock. They conclude that the mammalian Per genes are not only light-responsive components of the circadian oscillator but also are involved in resetting of the circadian clock.