Benchmark for quantitative characterization of circadian clock cycles.

Understanding circadian clock mechanisms is fundamental in order to counteract the harmful effects of clock malfunctioning and associated diseases. Biochemical, genetic and systems biology approaches have provided invaluable information on the mechanisms of the circadian clock, from which many mathematical models have been developed to understand the dynamics and quantitative properties of the circadian oscillator. To better analyze and compare quantitatively all these circadian cycles, we propose a method based on a previously proposed circadian cycle segmentation into stages.

[Harmonic oscillations of circadian rhythms come out of the shadows].

About 40 % of the liver transcriptome display a circadian expression. Recently, harmonic oscillations of the circadian rhythm and independent of the circadian clock have been identified. Transcripts oscillating with a 12h period are involved in fundamental and ubiquitous cellular mechanisms such as proteostasis, lipid metabolism or RNA metabolism.

Cycle dynamics and synchronization in a coupled network of peripheral circadian clocks.

The intercellular interactions between peripheral circadian clocks, located in tissues and organs other than the suprachiasmatic nuclei of the hypothalamus, are still very poorly understood. We propose a theoretical and computational study of the coupling between two or more clocks, using a calibrated, reduced model of the circadian clock to describe some synchronization properties between peripheral cellular clocks. Based on a piecewise linearization of the dynamics of the mutual CLOCK:BMAL1/PER:CRY inactivation term, we suggest a segmentation of the circadian cycle into six stages, to help analyse different types of synchronization between two clocks, including single stage duration, total period and maximal amplitudes.

KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism.

The mammalian circadian timing system and metabolism are highly interconnected, and disruption of this coupling is associated with negative health outcomes. Krüppel-like factors (KLFs) are transcription factors that govern metabolic homeostasis in various organs. Many KLFs show a circadian expression in the liver.

Model learning to identify systemic regulators of the peripheral circadian clock.

Motivation: Personalized medicine aims at providing patient-tailored therapeutics based on multi-type data toward improved treatment outcomes. Chronotherapy that consists in adapting drug administration to the patient's circadian rhythms may be improved by such approach. Recent clinical studies demonstrated large variability in patients' circadian coordination and optimal drug timing.

A detailed map of coupled circadian clock and cell cycle with qualitative dynamics validation.

Background: The temporal coordination of biological processes by the circadian clock is an important mechanism, and its disruption has negative health outcomes, including cancer. Experimental and theoretical evidence suggests that the oscillators driving the circadian clock and the cell cycle are coupled through phase locking.

Results: We present a detailed and documented map of known mechanisms related to the regulation of the circadian clock, and its coupling with an existing cell cycle map which includes main interactions of the mammalian cell cycle.

MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice.

A large number of hepatic functions are regulated by the circadian clock and recent evidence suggests that clock disruption could be a risk factor for liver complications. The circadian transcription factor Krüppel like factor 10 (KLF10) has been involved in liver metabolism as well as cellular inflammatory and death pathways. Here, we show that hepatic steatosis and inflammation display diurnal rhythmicity in mice developing steatohepatitis upon feeding with a methionine and choline deficient diet (MCDD).

Sexual Dimorphism in Circadian Physiology Is Altered in LXRα Deficient Mice.

The mammalian circadian timing system coordinates key molecular, cellular and physiological processes along the 24-h cycle. Accumulating evidence suggests that many clock-controlled processes display a sexual dimorphism. In mammals this is well exemplified by the difference between the male and female circadian patterns of glucocorticoid hormone secretion and clock gene expression.

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.

Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level.

Functional genomics identify Birc5/survivin as a candidate gene involved in the chronotoxicity of cyclin-dependent kinase inhibitors.

The circadian timing system orchestrates most of mammalian physiology and behavior in synchrony with the external light/dark cycle. This regulation is achieved through endogenous clocks present in virtually all body cells, where they control key cellular processes, including metabolism, transport, and the cell cycle. Consistently, it has been observed in preclinical cancer models that both the efficacy and toxicity of most chemotherapeutic drugs depend on their time of administration.

The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism.

Mutations of clock genes can lead to diabetes and obesity. REV-ERBα, a nuclear receptor involved in the circadian clockwork, has been shown to control lipid metabolism. To gain insight into the role of REV-ERBα in energy homeostasis in vivo, we explored daily metabolism of carbohydrates and lipids in chow-fed, unfed, or high-fat-fed Rev-erbα(-/-) mice and their wild-type littermates.

Cancer inhibition through circadian reprogramming of tumor transcriptome with meal timing.

Circadian disruption accelerates cancer progression, whereas circadian reinforcement could halt it. Mice with P03 pancreatic adenocarcinoma (n = 77) were synchronized and fed ad libitum (AL) or with meal timing (MT) from Zeitgeber time (ZT) 2 to ZT6 with normal or fat diet. Tumor gene expression profiling was determined with DNA microarrays at endogenous circadian time (CT) 4 and CT16.

Kruppel-like factor KLF10 is a link between the circadian clock and metabolism in liver.

The circadian timing system coordinates many aspects of mammalian physiology and behavior in synchrony with the external light/dark cycle. These rhythms are driven by endogenous molecular clocks present in most body cells. Many clock outputs are transcriptional regulators, suggesting that clock genes primarily control physiology through indirect pathways.

How nuclear receptors tell time.

Most organisms adapt their behavior and physiology to the daily changes in their environment through internal ( approximately 24 h) circadian clocks. In mammals, this time-keeping system is organized hierarchically, with a master clock located in the suprachiasmatic nuclei of the hypothalamus that is reset by light, and that, in turn, coordinates the oscillation of local clocks found in all cells. Central and peripheral clocks control, in a highly tissue-specific manner, hundreds of target genes, resulting in the circadian regulation of most physiological processes.

Deficiency of angiotensin type 2 receptor rescues obesity but not hypertension induced by overexpression of angiotensinogen in adipose tissue.

Increased angiotensinogen (AGT) production by white adipose tissue has been related to not only obesity but also hypertension. Several studies have highlighted the importance of the angiotensin II type 2 receptor (AT2) in the regulation of blood pressure and fat mass, but the relevance of this transporter in a physiopathological model of increased AGT production, as it occurs in obesity, has not yet been investigated. We used transgenic mice that display either a deletion of AT2 (AT2 KO), an overexpression of AGT (OVEX), or both compound mutants (KOVEX).

The nuclear hormone receptor family round the clock.

Daily rhythms in behavior and physiology are observed in most organisms. These rhythms are controlled by internal self-sustained circadian ( approximately 24 h) clocks, which are present in virtually all cells. The 24-h oscillations are generated by a molecular mechanism entrained by external or internal time cues and which, in turn, regulate rhythmic outputs.

Altered Stra13 and Dec2 circadian gene expression in hypoxic cells.

The circadian system regulates rhythmically most of the mammalian physiology in synchrony with the environmental light/dark cycle. Alteration of circadian clock gene expression has been associated with tumour progression but the molecular links between the two mechanisms remain poorly defined. Here we show that Stra13 and Dec2, two circadian transcriptional regulators which play a crucial role in cell proliferation and apoptosis are overexpressed and no longer rhythmic in serum shocked fibroblasts treated with CoCl(2,) a substitute of hypoxia.

The circadian clock component BMAL1 is a critical regulator of p21WAF1/CIP1 expression and hepatocyte proliferation.

Most living organisms show circadian (approximately 24 h) rhythms in physiology and behavior. These oscillations are generated by endogenous circadian clocks, present in virtually all cells where they control key biological processes. Although circadian gating of mitosis has been reported for many years in some peripheral tissues, the underlying molecular mechanisms have remained poorly understood.

Expression levels of estrogen receptor beta are modulated by components of the molecular clock.

Circadian regulation of gene expression plays a major role in health and disease. The precise role of the circadian system remains to be clarified, but it is known that circadian proteins generate physiological rhythms in organisms by regulating clock-controlled target genes. The estrogen receptor beta (ERbeta) is, together with ERalpha, a member of the nuclear receptor superfamily and a key mediator of estrogen action.

The adipose renin-angiotensin system modulates systemic markers of insulin sensitivity and activates the intrarenal renin-angiotensin system.

Background: The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism.

Methods And Results: A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO), mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO), and mice overexpressing Agt in adipose tissue (aP2-Agt) was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased.

In vivo evidence for a role of adipose tissue SR-BI in the nutritional and hormonal regulation of adiposity and cholesterol homeostasis.

Objectives: This study examines the role of insulin and angiotensin II in high-density lipoprotein (HDL) metabolism by focusing on the regulation and function of scavenger receptor type-BI (SR-BI) in adipose tissue.

Methods And Results: Insulin or angiotensin II injection in wild-type mice induced a decrease in circulating HDL and it was associated with the translocation of SR-BI from intracellular sites to the plasma membrane of adipose tissue. Refeeding upregulated adipose HDL selective cholesteryl esters uptake and SR-BI proteins through transcriptional and posttranscriptional mechanisms.