Genome-wide transcriptional orchestration of circadian rhythms in Drosophila

Circadian rhythms govern the behavior, physiology, and metabolism of living organisms. Recent studies have revealed the role of several genes in the clock mechanism both in Drosophila and in mammals. To study how gene expression is globally regulated by the clock mechanism, we used a high density oligonucleotide probe array (GeneChip) to profile gene expression patterns in Drosophila under light-dark and constant dark conditions. We found 712 genes showing a daily fluctuation in mRNA levels under light-dark conditions, and among these the expression of 115 genes was still cycling in constant darkness, i.e. under free-running conditions. Unexpectedly the expression of a large number of genes cycled exclusively under constant darkness. We found that cycling in most of these genes was lost in the arrhythmic Clock (Clk) mutant under light-dark conditions. Expression of periodically regulated genes is coordinated locally on chromosomes where small clusters of genes are regulated jointly. Our findings reveal that many genes involved in diverse functions are under circadian control and reveal the complexity of circadian gene expression in Drosophila.     

Type 2 diabetes disrupts circadian orchestration of lipid metabolism and membrane fluidity in human pancreatic islets

Recent evidence suggests that circadian clocks ensure temporal orchestration of lipid homeostasis and play a role in pathophysiology of metabolic diseases in humans, including type 2 diabetes (T2D). Nevertheless, circadian regulation of lipid metabolism in human pancreatic islets has not been explored. Employing lipidomic analyses, we conducted temporal profiling in human pancreatic islets derived from 10 nondiabetic (ND) and 6 T2D donors. Among 329 detected lipid species across 8 major lipid classes, 5% exhibited circadian rhythmicity in ND human islets synchronized in vitro. Two-time point-based lipidomic analyses in T2D human islets revealed global and temporal alterations in phospho- and sphingolipids. Key enzymes regulating turnover of sphingolipids were rhythmically expressed in ND islets and exhibited altered levels in ND islets bearing disrupted clocks and in T2D islets. Strikingly, cellular membrane fluidity, measured by a Nile Red derivative NR12S, was reduced in plasma membrane of T2D diabetic human islets, in ND donors’ islets with disrupted circadian clockwork, or treated with sphingolipid pathway modulators. Moreover, inhibiting the glycosphingolipid biosynthesis led to strong reduction of insulin secretion triggered by glucose or KCl, whereas inhibiting earlier steps of de novo ceramide synthesis resulted in milder inhibitory effect on insulin secretion by ND islets. Our data suggest that circadian clocks operative in human pancreatic islets are required for temporal orchestration of lipid homeostasis, and that perturbation of temporal regulation of the islet lipid metabolism upon T2D leads to altered insulin secretion and membrane fluidity. These phenotypes were recapitulated in ND islets bearing disrupted clocks.

A study of circadian regulation of lipid metabolism in human pancreatic islets reveals that Type 2 Diabetes leads to global and temporal alterations of phospholipid and sphingolipid metabolism in islets, resulting in decreased membrane fluidity and insulin secretion defects.     

Molecular mechanisms underlying the Arabidopsis circadian clock

A wide range of biological processes exhibit circadian rhythm, enabling plants to adapt to the environmental day-night cycle. This rhythm is generated by the so-called 'circadian clock'. Although a number of genetic approaches have identified >25 clock-associated genes involved in the Arabidopsis clock mechanism, the molecular functions of a large part of these genes are not known. Recent comprehensive studies have revealed the molecular functions of several key clock-associated proteins. This progress has provided mechanistic insights into how key clock-associated proteins are integrated, and may help in understanding the essence of the clock's molecular mechanisms.     

Cell-autonomous hepatic circadian clock regulates polyamine synthesis

Comment on: Atwood A, et al. Proc Natl Acad Sci U S A 2011; 108:18560-5.     

Molecular mechanisms of entrainment in the Neurospora circadian clock

Light and temperature are 2 of the most important environmental influences on all circadian clocks, and Neurospora provides an excellent system for understanding their effects. Progress made in the past decade has led to a basic molecular understanding of how the Neurospora clock works and how environmental factors influence it. The purpose of this review is to summarize what we currently know about the molecular mechanism of light and temperature entrainment in Neurospora.     

动物昼夜生物钟的分子机制

动物的昼夜生物钟是一种十分重要的生物节律,对生物对环境的适应有着重要的意义。昼夜节律是一种综合适应,它体现在个体、器官、组织等不同的水平上。最近20几年来．人们通过对果蝇和鼠的昼夜生物钟振荡子的研究,逐渐揭示了动物生物钟的负反馈回路的分子机制。     

Serotonin and the orchestration of energy balance

The phylogenetically ancient signaling molecule serotonin is found in all species that possess nervous systems and orchestrates diverse behavioral and physiological processes in the service of energy balance. In some instances, the manner in which serotonin signaling influences these processes appears comparable among invertebrate and vertebrate species. Within mammalian species, central nervous system serotonergic signaling influences both behavioral and physiological determinants of energy balance. Within the gastrointestinal tract, serotonin mediates diverse sensory, motor, and secretory functions. Further examinations of serotonergic influences on peripheral organ systems are likely to uncover novel functions consistent with an apparently pervasive association between serotonergic signaling and physiological substrates of energy balance.     

Molecular mechanisms of hepatic apoptosis

Apoptosis is a prominent feature of liver diseases. Causative factors such as alcohol, viruses, toxic bile acids, fatty acids, drugs, and immune response, can induce apoptotic cell death via membrane receptors and intracellular stress. Apoptotic signaling network, including membrane death receptor-mediated cascade, reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, lysosomal permeabilization, and mitochondrial dysfunction, is intermixed each other, but one mechanism may dominate at a particular stage. Mechanisms of hepatic apoptosis are complicated by multiple signaling pathways. The progression of liver disease is affected by the balance between apoptotic and antiapoptotic capabilities. Therapeutic options of liver injury are impacted by the clear understanding toward mechanisms of hepatic apoptosis.