Increased susceptibility of circadian clock mutant mice to metabolic diseases has led to the idea that a molecular clock is necessary for metabolic homeostasis. However, these mice often lack a ...normal feeding-fasting cycle. We tested whether time-restricted feeding (TRF) could prevent obesity and metabolic syndrome in whole-body Cry1;Cry2 and in liver-specific Bmal1 and Rev-erbα/β knockout mice. When provided access to food ad libitum, these mice rapidly gained weight and showed genotype-specific metabolic defects. However, when fed the same diet under TRF (food access restricted to 10 hr during the dark phase) they were protected from excessive weight gain and metabolic diseases. Transcriptome and metabolome analyses showed that TRF reduced the accumulation of hepatic lipids and enhanced cellular defenses against metabolic stress. These results suggest that the circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding and fasting and by maintaining balance between nutrient and cellular stress responses.
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•TRF protects clock mutant mice from obesity without changes in activity or calories•TRF restores rhythms in feeding-fasting, metabolic, and nutrient-sensing pathways•TRF prevents fatty liver, dyslipidemia, and glucose intolerance in clock mutant mice•TRF transcriptional program activates cellular homeostasis maintenance pathways
Chaix et al. show that time-restricted feeding (TRF; 10 hr access to food during the active phase) can improve metabolic health in mice with a compromised circadian clock. Their results point to metabolic dysfunction as secondary to disrupted behavioral rhythms (e.g., feeding-fasting), and which can be redressed by TRF.
Daily rhythms in behavior, physiology, and metabolism are an integral part of homeostasis. These rhythms emerge from interactions between endogenous circadian clocks and ambient light-dark cycles, ...sleep-activity cycles, and eating-fasting cycles. Nearly the entire primate genome shows daily rhythms in expression in tissue- and locus-specific manners. These molecular rhythms modulate several key aspects of cellular and tissue function with profound implications in public health, disease prevention, and disease management. In modern societies light at night disrupts circadian rhythms, leading to further disruption of sleep-activity and eating-fasting cycles. While acute circadian disruption may cause transient discomfort or exacerbate chronic diseases, chronic circadian disruption can enhance risks for numerous diseases. The molecular understanding of circadian rhythms is opening new therapeutic frontiers placing the circadian clock in a central role. Here, we review recent advancements on how to enhance our circadian clock through behavioral interventions, timing of drug administration, and pharmacological targeting of circadian clock components that are already providing new preventive and therapeutic strategies for several diseases, including metabolic syndrome and cancer.
Although circadian rhythm disruption (CRD) was typically considered to be a risk for chronic diseases solely for shift workers (∼20% of workforce), new epidemiological data suggest more than 80% of the population may be living a shift work lifestyle and thus are at elevated risk for chronic diseases.
Acute CRD compromises health with temporary physical challenges and may be a trigger for underlying latent diseases. Chronic CRD raises the risk for cancer along with a range of diseases affecting the central nervous system, immune and reproductive systems, metabolic organs, endocrine functions, and cardiovascular health.
Recent progress in understanding the molecular mechanisms of circadian timing and diurnal rhythms of tissue-specific gene products has generated testable hypotheses for how the circadian timing system optimizes health and, conversely, how circadian disruption leads to diseases.
Leveraging circadian rhythms to prevent, manage, and treat diseases involves three major strategies: optimizing the circadian lifestyle (‘training the clock’), optimizing timing of therapies (‘clocking the drugs’), and targeting specific circadian clock components (‘drugging the clock’).
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Dosing time accounts for a large variability in efficacy and/or toxicity for many drugs. Therefore, chronotherapy has been shown to effectively improve drug efficacy and to reduce ...drug toxicity. Circadian changes in pharmacokinetics and pharmacodynamics (drug target) are two essential sources of time-varying drug effects. Pharmacokinetics determines the drug and metabolite concentrations (exposure) in target tissues/organs, thereby impacting drug efficacy and toxicity. Pharmacokinetic processes are generally divided into drug absorption, distribution, metabolism and excretion (so-called “ADME”). Recent years of studies have revealed circadian (~24 h) rhythms in ADME processes, and clarified the underlying mechanisms related to circadian clock regulation. Furthermore, there is accumulating evidence that circadian pharmacokinetics can be translated to chronotoxicity and chronoefficacy. In this article, we review circadian rhythms in pharmacokinetic behaviors along with the underlying mechanisms. We also discuss the correlations of circadian pharmacokinetics with chronotoxicity and chronoefficacy.
The circadian clock is a biological mechanism that dictates an array of rhythmic physiological processes. Virtually all cells contain a functional clock whose disruption results in altered ...timekeeping and detrimental systemic effects, including cancer. Recent advances have connected genetic disruption of the clock with multiple transcriptional and signaling networks controlling tumor initiation and progression. An additional feature of this circadian control relies on cellular metabolism, both within the tumor microenvironment and the organism systemically. A discussion of major advances related to cancer metabolism and the circadian clock will be outlined, including new efforts related to metabolic flux of transformed cells, metabolic heterogeneity of tumors, and the implications of circadian control of these pathways.
The circadian clock is a biological pacemaker mechanism that precisely controls rhythms in behavior and physiological functions controlling endocrinology, metabolism, and immune response.Disruption of circadian rhythms has been reported to adversely alter normal physiology and results in disorders linked to metabolism, mood regulation, sleep behavior, and cancer.Clinical data has shown that mutations and changes in expression of core clock genes is reported in several human cancers.Use of genetic mouse models and cell lines have delineated the crosstalk of the circadian clock with several pathways linked to oncogenes and tumor suppressors, such as c-Myc, Ras, PTEN, and p53.The circadian clock governs metabolic pathways regulating glucose utilization, amino acid uptake, lipogenesis, and β-oxidation. Therefore, deregulation of circadian rhythms impinges on metabolism and subsequent proliferation of cancer cells, which can provide new avenues for therapeutic intervention.
After three decades of the amazing progress made on molecular studies of plant–microbe interactions (MPMI), we have begun to ask ourselves “what are the major questions still remaining?” as if the ...puzzle has only a few pieces missing. Such an exercise has ultimately led to the realization that we still have many more questions than answers. Therefore, it would be an impossible task for us to project a coherent “big picture” of the MPMI field in a single review. Instead, we provide our opinions on where we would like to go in our research as an invitation to the community to join us in this exploration of new MPMI frontiers.
We summarize recent progress and share our perspective in the areas of extracellular immunity, sensing of immunogenic signals by cell surface and intracellular immune receptors, heterogeneity of immune responses within tissues and cells, translational regulation as a critical layer of control in plant immune induction, and the role of the circadian clock in breaking the disease triangle in plants.
The circadian clock orchestrates rhythms in physiology and behavior, allowing organismal adaptation to daily environmental changes. While food intake profoundly influences diurnal rhythms in the ...liver, how nutritional challenges are differentially interpreted by distinct tissue-specific clocks remains poorly explored. Ketogenic diet (KD) is considered to have metabolic and therapeutic value, though its impact on circadian homeostasis is virtually unknown. We show that KD has profound and differential effects on liver and intestine clocks. Specifically, the amplitude of clock-controlled genes and BMAL1 chromatin recruitment are drastically altered by KD in the liver, but not in the intestine. KD induces nuclear accumulation of PPARα in both tissues but with different circadian phase. Also, gut and liver clocks respond differently to carbohydrate supplementation to KD. Importantly, KD induces serum and intestinal β-hydroxyl-butyrate levels to robustly oscillate in a circadian manner, an event coupled to tissue-specific cyclic histone deacetylase (HDAC) activity and histone acetylation.
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•KD induces tissue-specific reprogramming of the circadian clock in liver and gut•KD induces an increase in liver BMAL1 chromatin recruitment and amplitude of CCGs•KD drives tissue-specific oscillation of PPARα and its target genes•Oscillation of βOHB in gut and serum parallels gut-specific cycling of H3 acetylation
Tognini et al. reveal how a ketogenic diet (KD) differently affects liver and intestine circadian clocks and drives tissue-specific oscillation of PPARα and its target genes. Serum and intestine βOHB shows a unique diurnal rhythmicity, associated with daily epigenetic changes exclusively in the gut.
Photic and non-photic stimuli have been shown to shift the phase of the human circadian clock. We examined how photic and non-photic time cues may be combined by the human circadian system by ...assessing the phase advancing effects of one evening dose of exogenous melatonin, alone and in combination with one session of morning bright light exposure.
Randomized placebo-controlled double-blind circadian protocol. The effects of four conditions, dim light (∼1.9 lux, ∼0.6 Watts/m(2))-placebo, dim light-melatonin (5 mg), bright light (∼3000 lux, ∼7 Watts/m(2))-placebo, and bright light-melatonin on circadian phase was assessed by the change in the salivary dim light melatonin onset (DLMO) prior to and following treatment under constant routine conditions. Melatonin or placebo was administered 5.75 h prior to habitual bedtime and 3 h of bright light exposure started 1 h prior to habitual wake time.
Sleep and chronobiology laboratory environment free of time cues.
Thirty-six healthy participants (18 females) aged 22 ± 4 y (mean ± SD).
Morning bright light combined with early evening exogenous melatonin induced a greater phase advance of the DLMO than either treatment alone. Bright light alone and melatonin alone induced similar phase advances.
Information from light and melatonin appear to be combined by the human circadian clock. The ability to combine circadian time cues has important implications for understanding fundamental physiological principles of the human circadian timing system. Knowledge of such principles is important for designing effective countermeasures for phase-shifting the human circadian clock to adapt to jet lag, shift work, and for designing effective treatments for circadian sleep-wakefulness disorders.
To accommodate daily recurring environmental changes, animals show cyclic variations in behaviour and physiology, which include prominent behavioural states such as sleep-wake cycles but also a host ...of less conspicuous oscillations in neurological, metabolic, endocrine, cardiovascular and immune functions. Circadian rhythmicity is created endogenously by genetically encoded molecular clocks, whose components cooperate to generate cyclic changes in their own abundance and activity, with a periodicity of about a day. Throughout the body, such molecular clocks convey temporal control to the function of organs and tissues by regulating pertinent downstream programmes. Synchrony between the different circadian oscillators and resonance with the solar day is largely enabled by a neural pacemaker, which is directly responsive to certain environmental cues and able to transmit internal time-of-day representations to the entire body. In this Review, we discuss aspects of the circadian clock in Drosophila melanogaster and mammals, including the components of these molecular oscillators, the function and mechanisms of action of central and peripheral clocks, their synchronization and their relevance to human health.
The liver circadian clock is reprogrammed by nutritional challenge through the rewiring of specific transcriptional pathways. As the gut microbiota is tightly connected to host metabolism, whose ...coordination is governed by the circadian clock, we explored whether gut microbes influence circadian homeostasis and how they distally control the peripheral clock in the liver. Using fecal transplant procedures we reveal that, in response to high‐fat diet, the gut microbiota drives PPARγ‐mediated activation of newly oscillatory transcriptional programs in the liver. Moreover, antibiotics treatment prevents PPARγ‐driven transcription in the liver, underscoring the essential role of gut microbes in clock reprogramming and hepatic circadian homeostasis. Thus, a specific molecular signature characterizes the influence of the gut microbiome in the liver, leading to the transcriptional rewiring of hepatic metabolism.
Synopsis
High‐fat diet‐induced reprogramming in the mouse liver is driven by the gut microbiota through PPARγ. The microbiota in the gut exerts a distal effect on an otherwise non‐cyclic liver metabolic and transcriptional program.
Gut microbes distally influence the liver circadian clock.
High‐fat diet microbiota‐driven transcriptional reprogramming is mediated by PPARγ.
Antibiotic treatment prevents HFD‐induced reprogramming of the liver clock.
High‐fat diet‐induced reprogramming in the mouse liver is driven by the gut microbiota through PPARγ. The microbiota in the gut exerts a distal effect on an otherwise non‐cyclic liver metabolic and transcriptional program.
The LATE ELONGATED HYPOCOTYL (LHY) transcription factor functions as part of the oscillatory mechanism of the Arabidopsis circadian clock. This paper reports the genome-wide analysis of its binding ...targets and reveals a role in the control of abscisic acid (ABA) biosynthesis and downstream responses.
LHY directly repressed expression of 9-cis-epoxycarotenoid dioxygenase enzymes, which catalyse the rate-limiting step of ABA biosynthesis. This suggested a mechanism for the circadian control of ABA accumulation in wild-type plants. Consistent with this hypothesis, ABA accumulated rhythmically in wild-type plants, peaking in the evening. LHY-overexpressing plants had reduced levels of ABA under drought stress, whereas loss-of-function mutants exhibited an altered rhythm of ABA accumulation.
LHY also bound the promoter of multiple components of ABA signalling pathways, suggesting that it may also act to regulate responses downstream of the hormone. LHY promoted expression of ABA-responsive genes responsible for increased tolerance to drought and osmotic stress but alleviated the inhibitory effect of ABA on seed germination and plant growth.
This study reveals a complex interaction between the circadian clock and ABA pathways, which is likely to make an important contribution to plant performance under drought and osmotic stress conditions.
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