Diurnal rhythms of autophagy: implications for cell biology and human disease

Autophagy is a key mechanism for cell survival under conditions of nutrient limitation. On the organismal level, autophagy is essential for survival of lower eukaryotes during extended periods of starvation, and it is induced in mammals during short-term starvation. As a consequence of the induction of autophagy during short periods of fasting, animals experience diurnal rhythms of autophagy in concert with their circadian cycle. Autophagy has also been identified as a component of the metabolic cycle of yeast, an ultradian rhythm that bears many similarities to the circadian rhythm of plants, flies and mammals. The circadian clock, which is present in almost all mammalian cell types studied to date, temporally regulates expression of multiple genes, gating cell processes such as nutrient uptake, glycolysis, and proliferation, to particular times of day. Whether the circadian clock directly regulates autophagy in mammalian cells, or whether autophagy may play a role in the cycling of mammalian cell clocks is not yet clear. Nevertheless, the relationship between circadian cycles and autophagy is an intriguing area for future study and has implications for multiple human diseases, including aging, neurodegeneration and cancer.     

Diurnal rhythms of autophagy: Implications for cell biology and human disease

Autophagy is a key mechanism for cell survival under conditions of nutrient limitation. On the organismal level, autophagy is essential for survival of lower eukaryotes during extended periods of starvation, and it is induced in mammals during short-term starvation. As a consequence of the induction of autophagy during short periods of fasting, animals experience diurnal rhythms of autophagy in concert with their circadian cycle. Autophagy has also been identified as a component of the metabolic cycle of yeast, an ultradian rhythm that bears many similarities to the circadian rhythm of plants, flies, and mammals. The circadian clock, which is present in almost all mammalian cell types studied to date, temporally regulates expression of multiple genes, gating cell processes such as nutrient uptake, glycolysis, and proliferation, to particular times of day. Whether the circadian clock directly regulates autophagy in mammalian cells, or whether autophagy may play a role in the cycling of mammalian cell clocks is not yet clear. Nevertheless, the relationship between circadian cycles and autophagy is an intriguing area for future study and has implications for multiple human diseases, including aging, neurodegeneration, and cancer.     

Differential roles of breakfast and supper in rats of a daily three-meal schedule upon circadian regulation and physiology

The timing of meals has been suggested to play an important role in circadian regulation and metabolic health. Three meals a day is a well-established human feeding habit, which in today's lifestyle may or may not be followed. The aim of this study was to test whether the absence of breakfast or supper significantly affects the circadian system and physiological function. The authors developed a rat model for their daily three meals study, whereby animals were divided into three groups (three meals, TM; no first meal, NF; no last meal, NL) all fed with the same amount of food every day. Rats in the NF group displayed significantly decreased levels of plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose in the activity phase, accompanied by delayed circadian phases of hepatic peripheral clock and downstream metabolic genes. Rats in the NL group showed lower concentration of plasma TC, HDL-C, and glucose in the rest phase, plus reduced adipose tissue accumulation and body weight gain. Real-time polymerase chain reaction (PCR) analysis indicated an attenuated rhythm in the food-entraining pathway, including down-regulated expression of the clock genes Per2, Bmal1, and Rev-erbα, which may further contribute to the delayed and decreased expression of FAS in lipogenesis in this group. Our findings are consistent with the conclusion that the daily first meal determines the circadian phasing of peripheral clocks, such as in the liver, whereas the daily last meal tightly couples to lipid metabolism and adipose tissue accumulation, which suggests differential physiological effects and function of the respective meal timings.     

Identification of an Annexin-Like Protein and Its Possible Role in the Aplysia Eye Circadian System

Abstract: Light and serotonin regulate the phase of the circadian rhythm of the isolated eye of Aplysia . To screen for possible protein components of the eye circadian oscillator, we identified a number of proteins whose synthesis was altered in opposite ways by light and serotonin. The cellular function of one of these proteins was investigated by obtaining a partial amino acid sequence of it and by examining its immunoreactivity. A 38-amino acid sequence was obtained from a 40-kDa (isoelectric point 5.6) protein. A greater than 60% amino acid identity existed between this sequence and sequences of a family of calcium/phospholipid-binding proteins called annexins. Furthermore, the 40-kDa protein reacted with antibodies generated against a conserved amino acid sequence of annexins and with antibodies raised against human annexin I. The identification of the 40-kDa, light- and serotonin-regulated protein as an annexin led us to hypothesize that arachidonic acid metabolism plays a role in the Aplysia eye circadian system. To test this hypothesis, we examined the ability of an inhibitor of the arachidonic acid metabolic pathway to perturb the eye rhythm. Pulse treatments of isolated eyes with a lipoxygenase inhibitor, nordihydroguaiaretic acid, phase shifted the rhythm. The phase-shifting ability of nordihydroguaiaretic acid suggests that arachidonic acid and some of its metabolites may play a role in the eye circadian system. The results of our studies raise the possibility that links may exist between the 40-kDa annexin-like protein, arachidonic acid metabolism, and the circadian oscillator.     

Nanomolar melatonin enhances nNOS expression and controls HaCaT-cells bioenergetics

A novel role of melatonin was unveiled, using immortalized human keratinocyte cells (HaCaT) as a model system. Within a time window compatible with its circadian rhythm, melatonin at nanomolar concentration raised both the expression level of the neuronal nitric oxide synthase mRNA and the nitric oxide oxidation products, nitrite and nitrate. On the same time scale, a depression of the mitochondrial membrane potential was detected together with a decrease of the oxidative phosphorylation efficiency, compensated by glycolysis as testified by an increased production of lactate. The melatonin concentration, ～ nmolar, inducing the bioenergetic effects and their time dependence, both suggest that the observed nitric oxide-induced mitochondrial changes might play a role in the metabolic pathways characterizing the circadian melatonin chemistry.     

哺乳动物生物钟与能量代谢的相关研究进展

生物钟广泛存在于各种生物体中,是生命体的一种内源调节机制。哺乳动物生物钟系统与机体营养代谢和能量平衡有着密切的关系。概述了生物钟系统通过营养途径、限速酶途径、核受体途径对哺乳动物机体代谢活动和能量平衡的调控,以及哺乳动物代谢稳态对生物钟系统的影响,从而为从生物钟调控的角度治疗和防控代谢综合征提供新的思路。     

Circadian systems and metabolism

Circadian systems direct many metabolic parameters and, at the same time, they appear to be exquisitely shielded from metabolic variations. Although the recent decade of circadian research has brought insights into how circadian periodicity may be generated at the molecular level, little is known about the relationship between this molecular feedback loop and metabolism both at the cellular and at the organismic level. In this theoretical paper, we conjecture about the interdependence between circadian rhythmicity and metabolism. A mathematical model based on the chemical reactions of photosynthesis demonstrates that metabolism as such may generate rhythmicity in the circadian range. Two additional models look at the possible function of feedback loops outside of the circadian oscillator. These feedback loops contribute to the robustness and sustainability of circadian oscillations and to compensation for long- and short-term metabolic variations. The specific circadian property of temperature compensation is put into the context of metabolism. As such, it represents a general compensatory mechanism that shields the clock from metabolic variations.     

Recent data about the role of hypothalamic suprachiasmatic nucleus in circadian organization of physiological functions

The suprachiasmatic nucleus is the primary circadian pacemaker in mammals. In turn, the suprachiasmatic nucleus influences circadian physiology, endocrinology and behavior via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus circadian pacemaker may play an important role in psychiatric disorders and in psychotherapeutic drugs effect. In this review, we summarize data about the suprachiasmatic nuclei anatomy, physiology and pharmacological sensitivity.     

昼夜节律钟调控代谢的研究进展

生理和行为的昼夜节律性调控对健康生活是必需的。越来越多的流行病学和遗传学证据显示昼夜节律的破坏与代谢紊乱性疾病相关联。在分子水平上,昼夜节律受到时钟蛋白组成的转录一翻译负反馈环的调控。时钟蛋白通过以下两种途径调节代谢：首先,时钟蛋白作为转录因子直接调节一些代谢关键步骤的限速酶和代谢相关核受体的表达,其次作为代谢相关核受体的辅调节因子来激活或抑制其转录活性。虽然时钟蛋白对代谢途径的调节导致代谢物水平呈昼夜节律振荡,但是产生的代谢物反过来又可以影响昼夜节律钟基因的表达,进而影响昼夜节律钟。深入研究昼夜节律钟与代谢的交互调节可能为治疗某些代谢紊乱性疾病提供新的治疗方案。     

The circadian clock influences heart performance

Circadian clocks are believed to provide the selective advantage of anticipation, thus allowing organisms to respond efficiently to stimuli at the appropriate moment. Disrupted circadian rhythms have been found to affect a variety of basic physiological processes. However, the importance of the circadian clock in regulating heart performance remains undetermined. We hypothesized that the circadian clock plays a crucial role in heart performance through the anticipation of daily workload. Echocardiography was employed to monitor heart function and structure in mice in a noninvasive, real-time manner. In wild-type mice, both the ejection fraction (EF) and the shortening fraction (FS), two important markers of cardiac function, show diurnal variation. In addition, the amplitude of the EF and the FS enlarges in response to forced exercise in a time-dependent manner. The diurnal variations in EF and FS are altered in mice with disruptions in circadian clock genes and are significantly attenuated under an imposed light regimen. Furthermore, it shows that the overexpression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc1α) under control of the muscle creatine kinase (MCK) promoter inhibited clock gene expression in the heart and muscle and decreased the expression of peroxisome proliferator-activated receptor alpha (Pparα), metabolic genes glucose transporter (Glut4), and acetyl-coA synthetase (Acs1). Pgc1α overexpression abolished the diurnal variation of EF. We thus propose that PGC1α might play an important role in circadian-mediated, impaired cardiac function by regulating the circadian rhythm of metabolic genes.     

Biological rhythms,chronodisruption and chrono-enhancement: The role of physical activity as synchronizer in correcting steroids circadian rhythm in metabolic dysfunctions and cancer

ABSTRACT

Rhythms can be observed at all levels of the biologic integration in humans. The observation that a biological or physiological variable shows a circadian rhythm can be explained by several multifactorial systems including external (exogenous), internal (endogenous) and psychobiological (lifestyle) mechanisms. Our body clock can be synchronized with the environment by external factors, called “synchronizers”, i.e. the light–dark cycle, but it is also negatively influenced by some pathological conditions or factors, called “chronodisruptors,” i.e. aging or low physical activity (PA). The desynchronization of a 24-h rhythm in a chronic manner has been recently defined “chronodisruption” or “circadian disruption.” A very large number of hormonal variables, such as adrenal and gonadal stress steroids, are governed by circadian rhythmicity. Such hormones, in normal conditions, show a peak in the first part of the day, while their typical diurnal fluctuations are totally out of sync in subjects affected by cancer or metabolic diseases, such as obesity, diabetes and metabolic syndrome. In general, a flatter slope with altered peaks in cortisol and testosterone circadian rhythms has been observed in pathological individuals. PA, specifically chronic exercise, seems to play a key role as synchronizer for the whole circadian system in such pathologies even if specific data on steroids circadian pattern are still sparse and contradictory. Recently, it has been proposed that low-intensity chronic PA could be an effective intervention to decrease morning cortisol levels in pathological subjects. The standardization of all confounding factors is needed to reach more clear evidence-based results.     

Rev-erb alpha gives a time cue to metabolism

Normal physiological processes are under control of circadian rhythms. Moreover, certain pathological events, such as cardiovascular accidents (myocardial infarction, stroke) occur more frequently at specific times of the day. Recent observations demonstrate a causal relationship between alterations in circadian rhythmicity and metabolic disorders. Disruption of clock genes results in dyslipidemia, insulin resistance and obesity, all predisposing to atherosclerosis. The nuclear receptor Rev-erb alpha is part of the clock circuitry and plays an important role in keeping proper timing of the clock. Rev-erb alpha also regulates lipid metabolism, adipogenesis and vascular inflammation. Interestingly, Rev-erb alpha also cross-talks with several other nuclear receptors involved in energy homeostasis. Therefore Rev-erb alpha may serve to couple metabolic and circadian signals.     

Differential Roles of Breakfast and Supper in Rats of a Daily Three-Meal Schedule Upon Circadian Regulation and Physiology

The timing of meals has been suggested to play an important role in circadian regulation and metabolic health. Three meals a day is a well-established human feeding habit, which in today's lifestyle may or may not be followed. The aim of this study was to test whether the absence of breakfast or supper significantly affects the circadian system and physiological function. The authors developed a rat model for their daily three meals study, whereby animals were divided into three groups (three meals, TM; no first meal, NF; no last meal, NL) all fed with the same amount of food every day. Rats in the NF group displayed significantly decreased levels of plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose in the activity phase, accompanied by delayed circadian phases of hepatic peripheral clock and downstream metabolic genes. Rats in the NL group showed lower concentration of plasma TC, HDL-C, and glucose in the rest phase, plus reduced adipose tissue accumulation and body weight gain. Real-time polymerase chain reaction (PCR) analysis indicated an attenuated rhythm in the food-entraining pathway, including down-regulated expression of the clock genes Per2, Bmal1, and Rev-erbα, which may further contribute to the delayed and decreased expression of FAS in lipogenesis in this group. Our findings are consistent with the conclusion that the daily first meal determines the circadian phasing of peripheral clocks, such as in the liver, whereas the daily last meal tightly couples to lipid metabolism and adipose tissue accumulation, which suggests differential physiological effects and function of the respective meal timings. (Author correspondence: azwfu2003@yahoo.com.cn)     

The temporal organization of daily torpor and hibernation: circadian and circannual rhythms

Mammals and birds have evolved the ability to maintain a high and constant body temperature T_b over a wide range of ambient temperatures T_a using endogenous heat production. In many, especially small endotherms, cost for thermoregulatory heat production can exceed available energy; to overcome these energetic bottlenecks, they enter a state of torpor (a regulated reduction of T_b and metabolic rate). Since the occurrence of torpor in many species is a seasonal event and occurs at certain times of the day, we review whether circadian and circannual rhythms, important in the timing of biological events in active animals, also play an important role during torpor when T_b is reduced substantially and may even fall below 0°C. The two distinct patterns of torpor, hibernation (prolonged torpor) and daily torpor, differ substantially in their interaction with the circadian system. Daily torpor appears to be integrated into the normal circadian rhythm of activity and rest, although torpor is not restricted only to the normal rest phase of an animal. In contrast, hibernation can last for several days or even weeks, although torpor never spans the entire hibernation season, but is interrupted by periodic arousals and brief normothermic periods. Clearly, a day is no longer divided in activity and rest, and at first glance the role of the circadian system appears negligible. However, in several hibernators, arousals not only follow a regular pattern consistent with a circadian rhythm, but also are entrainable by external stimuli such as photoperiod and T_a. The extent of the interaction between the circadian and circannual system and hibernation varies among species. Biological rhythms of hibernators for which food availability appears to be predictable seasonally and that hibernate in deep and sealed burrows show little sensitivity to external stimuli during hibernation and hence little entrainability of arousal events. In contrast, opportunistic hibernators, which some times use arousals for foraging and hibernate in open and accessible hibernacula, are susceptible to external zeitgebers. In opportunistic hibernators, the circadian system plays a major role in maintaining synchrony between the normal day-night cycle and occasional foraging. Although the daily routine of activity and rest is abandoned during hibernation, the circadian system appears to remain functional, and there is little evidence it is significantly affected by low T_b. (Chronobiology International, 17(2), 103-128, 2000)