Peripheral Clocks Research Articles

A minimal model of peripheral clocks reveals differential circadian re-entrainment in aging.

The mammalian circadian system comprises a network of endogenous oscillators, spanning from the central clock in the brain to peripheral clocks in other organs. These clocks are tightly coordinated to orchestrate rhythmic physiological and behavioral functions. Dysregulation of these rhythms is a hallmark of aging, yet it remains unclear how age-related changes lead to more easily disrupted circadian rhythms. Using a two-population model of coupled oscillators that integrates the central clock and the peripheral clocks, we derive simple mean-field equations that can capture many aspects of the rich behavior found in the mammalian circadian system. We focus on three age-associated effects that have been posited to contribute to circadian misalignment: attenuated input from the sympathetic pathway, reduced responsiveness to light, and a decline in the expression of neurotransmitters. We find that the first two factors can significantly impede re-entrainment of the clocks following perturbation, while a weaker coupling within the central clock does not affect the recovery rate. Moreover, using our minimal model, we demonstrate the potential of using the feed-fast cycle as an effective intervention to accelerate circadian re-entrainment. These results highlight the importance of peripheral clocks in regulating the circadian rhythm and provide fresh insights into the complex interplay between aging and the resilience of the circadian system.

Effects of the neonatal intensive care environment on circadian health and development of preterm infants.

The circadian system in mammals ensures adaptation to the light-dark cycle on Earth and imposes 24-h rhythmicity on metabolic, physiological and behavioral processes. The central circadian pacemaker is located in the brain and is entrained by environmental signals called Zeitgebers. From here, neural, humoral and systemic signals drive rhythms in peripheral clocks in nearly every mammalian tissue. During pregnancy, disruption of the complex interplay between the mother's rhythmic signals and the fetal developing circadian system can lead to long-term health consequences in the offspring. When an infant is born very preterm, it loses the temporal signals received from the mother prematurely and becomes totally dependent on 24/7 care in the Neonatal Intensive Care Unit (NICU), where day/night rhythmicity is usually blurred. In this literature review, we provide an overview of the fetal and neonatal development of the circadian system, and short-term consequences of disruption of this process as occurs in the NICU environment. Moreover, we provide a theoretical and molecular framework of how this disruption could lead to later-life disease. Finally, we discuss studies that aim to improve health outcomes after preterm birth by studying the effects of enhancing rhythmicity in light and noise exposure.

Circadian rhythms in colonic function.

A rhythmic expression of clock genes occurs within the cells of multiple organs and tissues throughout the body, termed "peripheral clocks." Peripheral clocks are subject to entrainment by a multitude of factors, many of which are directly or indirectly controlled by the light-entrainable clock located in the suprachiasmatic nucleus of the hypothalamus. Peripheral clocks occur in the gastrointestinal tract, notably the epithelia whose functions include regulation of absorption, permeability, and secretion of hormones; and in the myenteric plexus, which is the intrinsic neural network principally responsible for the coordination of muscular activity in the gut. This review focuses on the physiological circadian variation of major colonic functions and their entraining mechanisms, including colonic motility, absorption, hormone secretion, permeability, and pain signalling. Pathophysiological states such as irritable bowel syndrome and ulcerative colitis and their interactions with circadian rhythmicity are also described. Finally, the classic circadian hormone melatonin is discussed, which is expressed in the gut in greater quantities than the pineal gland, and whose exogenous use has been of therapeutic interest in treating colonic pathophysiological states, including those exacerbated by chronic circadian disruption.

Research progresses on the effects of heavy metals on the circadian clock system.

Environmental pollution with heavy metals is widespread, thus increasing attention has been paid to their toxic effects. Recent studies have suggested that heavy metals may influence the expression of circadian clock genes. Almost all organs and tissues exhibit circadian rhythms. The normal circadian rhythm of an organism is maintained by the central and peripheral circadian clock. Thus, circadian rhythm disorders perturb normal physiological processes. Here, we review the effects of heavy metals, including manganese, copper, cadmium, and lead, on four core circadian clock genes, i.e.,ARNTL, CLOCK, PER, and CRY genes.

Is Diabetes Pre-coded in the Brain? Role of Hypothalamus, Addiction Network and Social Cognition

The hypothalamus, the master regulator of circadian rhythm, in association with peripheral clocks, play crucial roles in glucose metabolism. Impairment in cerebral sensing, uptake and processing of glucose has been suggested in various animal and human diabetic models. Diabetes Mellitus has been largely superseded by the discovery of insulin and insulin resistance. Expanding horizons of knowledge of the roles of the hypothalamus in glucose metabolism and the overlapping neural pathways of sugar addictionwith other classically described substance and behavioral addictions networks have again thrown some light on the cerebral theory of DM pathogenesis.

Clock genes regulate skeletal muscle energy metabolism through NAMPT/NAD+/SIRT1 following heavy-load exercise.

The biological clock is an invisible "clock" in the organism, which can regulate behavior, physiology, and biochemical reactions. However, the relationship between clock genes and energy metabolism in postexercise skeletal muscle is not well known. The purpose of this study was to determine the mechanisms through which peripheral clock genes regulate energy metabolism in skeletal muscle. We analyzed the rhythm of mRNA expression of the clock genes Bmal1 and Clock in skeletal muscle following heavy-load exercise and measured related indicators of mitochondrial structure and function. We obtained the following experimental results. First, heavy-load exercise induced loss of circadian rhythm of Bmal1 between ZT0 and ZT24, and the circadian rhythm of Clock was not restored between ZT0 and ZT72. Second, analysis of mitochondrial morphology in group E showed abnormal swelling and ridge structure damage at ZT0, which recovered somewhat at ZT24 and ZT48, and the damage had essentially disappeared by ZT72. Third, the expression of NAMPT/NAD+/SIRT1 signaling axis proteins in group E was abnormal at ZT0, the content of NAMPT and the activity of SIRT1 significantly increased, and the content of NAD+ significantly decreased. Fourth, the expression of BMAL1 and PGC-1α in group E significantly increased, whereas the ATP and ADP content, as well as the activities of COXII and COXIV, were significantly changed. Finally, the colocalization of BMAL1 and SIRT1 in group E was significantly upregulated at ZT0. These results suggest that the skeletal muscle clock gene Bmal1 may regulate the energy metabolism level of skeletal muscle after exercise through the NAMPT/NAD+/SIRT1 signaling pathway.

The SCN-HPA-Periphery Circadian Timing System: Mathematical Modeling of Clock Synchronization and the Effects of Photoperiod on Jetlag Adaptation.

Synchronizing the circadian timing system (CTS) to external light/dark cycles is crucial for homeostasis maintenance and environmental adaptation. The CTS is organized hierarchically, with the central pacemaker located in the suprachiasmatic nuclei (SCN) generating coherent oscillations that are entrained to light/dark cycles. These oscillations regulate the release of glucocorticoids by the hypothalamus-pituitary-adrenal (HPA) axis, which acts as a systemic entrainer of peripheral clocks throughout the body. The SCN adjusts its network plasticity in response to variations in photoperiod, leading to changes in the rhythmic release of glucocorticoids and ultimately impacting peripheral clocks. However, the effects of photoperiod-induced variations of glucocorticoids on the synchronization of peripheral clocks are not fully understood, and the interaction between jetlag adaption and photoperiod changes is unclear. This study presents a semi-mechanistic mathematical model to investigate how the CTS responds to changes in photoperiod. Specifically, the study focuses on the entrainment properties of a system composed of the SCN, HPA axis, and peripheral clocks. The results show that high-amplitude glucocorticoid rhythms lead to a more coherent phase distribution in the periphery. In addition, our study investigates the effect of photoperiod exposure on jetlag recovery time and phase shift, proposing different interventional strategies for eastward and westward jetlag. The findings suggest that decreasing photic exposure before jetlag during eastward traveling and after jetlag during westward traveling can accelerate jetlag readaptation. The study provides insights into the mechanisms of CTS organization and potential recovery strategies for transitions between time zones and lighting zones.

Non-visual and alerting impact of light on the physiology of human body

The human body and brain are affected by light both visually and non-visually. Light has extraordinary impact on large group of physiological capabilities, and encompass neuroendocrine regulation, sleep, alertness, cognition, and ocular reflexes, as well as phase-shifting and synchronization of the circadian framework. The blue light exposure is significant for keeping living organisms, cognitive performance prosperity and sharpness. The human eyes may suffer from excessive exposure of the blue light. The lack of light has a negative impact on sleep quality and alertness as well as mood, seasonal affective disorder and neurocognitive cycles. Early morning exposure to strong light delays the peak of melatonin production and alters cortisol, GH, PRL, and nocturnal vasopressin emission. Metabolic capabilities including the reducing levels of glucose resistance and diminished insulin sensitivity are horribly affected by night light exposure. Type 2 diabetes risk increases in an old populace due to the elevation in night light exposure. Ladies presented to night-light moves had sporadic monthly cycles that were much of the time related to dysmenorrhea and metabolic disorder insulin obstruction and liberation of glucose digestion. Estrus cycles, ovulation, sperm production, implantation, and the development of pregnancy are also affected by the desynchronizing effect of altered light signals on the circadian peripheral clocks in female and male conceptive tissues. DNA is harmed directly by UVB radiation. The present effort is to investigate and summarize the non-visual and alerting effect of light on the physiology of the human body.

Reciprocal regulation between the molecular clock and kidney injury.

Tubulointerstitial fibrosis is the common pathological substrate for many etiologies leading to chronic kidney disease. Although perturbations in the circadian rhythm have been associated with renal disease, the role of the molecular clock in the pathogenesis of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (unilateral ureteral obstruction, folic acid, and adenine nephrotoxicity), using genetically modified mice with selective deficiencies of the clock components Bmal1, Clock, and Cry We found that the molecular clock pathway was enriched in damaged tubular epithelial cells with marked metabolic alterations. In human tubular epithelial cells, TGFβ significantly altered the expression of clock components. Although Clock played a role in the macrophage-mediated inflammatory response, the combined absence of Cry1 and Cry2 was critical for the recruitment of neutrophils, correlating with a worsening of fibrosis and with a major shift in the expression of metabolism-related genes. These results support that renal damage disrupts the kidney peripheral molecular clock, which in turn promotes metabolic derangement linked to inflammatory and fibrotic responses.

Subcutaneous adipose tissue circadian gene expression: Relationship with insulin sensitivity, obesity, and the effect of weight-reducing dietary intervention

ObjectiveThe circadian rhythms are controlled by the central clock in the hypothalamic suprachiasmatic nuclei and by the peripheral clocks in tissues, including adipose tissue. The adipose tissue circadian clock may be associated with the regulation of insulin action; however, human data are limited. The aim of this study was to analyze the expression of subcutaneous adipose tissue circadian genes as they relate to obesity and insulin sensitivity before and after diet-induced weight loss. MethodsThe study group comprised 38 individuals who were overweight or obese. The individuals completed a 12-wk dietary intervention program. Hyperinsulinemic-euglycemic clamp and subcutaneous adipose tissue biopsy were performed before and after the program. Sixteen normal weight individuals were examined at baseline and served as a control group. ResultsAt baseline, individuals who were overweight/obese had lower adipose tissue expression of NR1D1, NR1D2, DBP, PER1, and PER2 than normal weight individuals. The expression of ARNTL, CLOCK, and CRY did not differ between the groups. A weight-reducing dietary intervention resulted in an increase in the expression of adipose tissue NR1D2 and DBP, which was positively related to insulin sensitivity both before (in the entire study group and in the subgroup of overweight/obese individuals) and after the dietary intervention. ConclusionsAdipose tissue circadian gene expression is decreased in obesity and this decrease may be partially reversed by dietary intervention. Among circadian genes, NR1D2 and DBP seem to be specifically associated with insulin action.

Chronic exposure to dim artificial light disrupts the daily rhythm in mitochondrial respiration in mouse suprachiasmatic nucleus

ABSTRACT Circadian rhythms of physiology, behavior, and metabolism have an endogenous 24 h period that synchronizes with environmental cycles of light/dark and food availability. Alterations in light cycles are stressful and disrupt such diurnal oscillations. Recently, we witnessed a sudden rise in studies describing the mechanisms behind the interaction between the key characteristics of mitochondrial functions, peripheral clocks, and stress responses. To our knowledge, there is no study in the suprachiasmatic nuclei (SCN) describing the dysregulated mitochondrial bioenergetics under abnormal lighting conditions, which is common in today’s modern world. Thus, we aimed to investigate the existence of daily changes in mitochondrial bioenergetics (respiratory control rate, RCR), mitochondrial abundance (mtDNA/nDNA), plasma corticosterone, and to test whether disturbances in the lighting conditions might influence such rhythms. To confirm this, mice were sacrificed, mitochondria were isolated from the suprachiasmatic nuclei in the brain and blood was collected, every 3 h at various time points zeitgeber time/circadian time, (0, 3, 6, 9, 12, 15, 18, 21, and 24 h) under 12:12 h light-dark (LD, 150 lux L: 0 lux D) cycle and chronic artificial dim lighting (LL, 5 lux: 5lux) conditions, of a 24 h period, respectively. Our results demonstrate the existence of robust daily rhythmicity in RCR, mtDNA/nDNA and plasma CORT under a normal LD cycle. However, these rhythms were significantly disrupted and clock genes expressions were dysregulated under chronic dim LL. Furthermore, mitochondrial abundance was significantly reduced during LL compared to their numbers under LD cycle. Our data demonstrate that the circadian clock regulates mitochondrial functions (RCR, number), essential for accomplishing daily energy demands and supply by the SCN neurons. Abnormal light exposure dysregulates mitochondrial functions in the SCN and may alter metabolism, resulting in obesity, diabetes, and other metabolic disorders. Therefore, properly designing lighting conditions in workplaces is essential to mitigate the adverse consequences of light on humans.

Chronotype and athletes’ performance in sports: A narrative review

The circadian system is managed by the suprachiasmatic nucleus, which is also called a master clock, and peripheral clocks spread all over the body. A complex system of neuronal, hormonal, and autonomous signals coordinates these clocks. However, this narrative review aimed to discuss the influence of circadian rhythms on the athlete’s performance, rate of perceived exertion, resynchronization, and aerobic and anaerobic exercise. An adequately timed wake-up is believed to play an essential role in an athlete’s performance. Based on the literature, chronotype appears to correlate with ratings of perceived exertion and fatigue scores, and morning types are less fatigued in the morning. When chronotype was evaluated, fatigue and vigor had time-by-group interactions. Swimmers with morning-type profiles showed lower fatigue scores before the (06:30 hour) time test than before the (18:30 hour) time test, while those with neither-type profiles had similar fatigue scores in both sessions. Vigor scores were also higher in the morning types than in the neither-types (17.9±7.1) before the morning test and (15.6±5.5) before the evening test. Studies have also shown that exercise enhances aerobic capacity based on the day. However, several reasons can lead to conflicting evidence regarding the chronotype effect on performance studies. Thus, more research is needed regarding the chronotype effect on athletes’ performance and the impact of time of day on muscle strength.

Effect of Withanolide-A on Mice Subjected to Simulated Chronic Jetlag/Shift Work

Objective: Circadian rhythm is maintained by central and peripheral clocks that regulate an organism’s physiological functions. Frequent trans-meridian travel, an irregular sleep-wake cycle, light exposure during the rest period, rotating shift work, and other factors cause desynchronization of central and peripheral clocks, impairing social and occupational behavior. Withanolide-A (WA) is used for its powerful nootropic and neuroprotective properties.Methods: Effects of 13 days consecutive pre-dosing of WA (10 μmol/kg/day) on circadian rhythm disruption caused due to 9 h advance-delay chronic jetlag light-dark shift was studied on re-entrainment rate analyzed through locomotor activity recording of mice using the ClockLab setup, learning and memory studied through Y-maze and Barnes maze tests. In the hippocampus, gene expression of <i>PER1</i> and <i>BDNF</i> was assessed using reverse transcription-quantitative polymerase chain reaction. The effect of WA treatment was also studied on superoxide dismutase, catalase, reactive oxygen species (ROS), and lipid peroxidation in hippocampal tissue.Results: The results showed that WA treatment leads to faster re-entrainment and better performance during Y-maze and Barnes maze tests. <i>PER1</i> and <i>BDNF</i> genes expression was upregulated in the treated group compared to chronic jetlag exposure groups in the hippocampus and suprachiasmatic nuclei. Moreover, the WA-treated group produced fewer ROS and superoxide radicals, and there was also less lipid peroxidation in the treated group.Conclusion: These results suggest that the WA may act as a chronobiotic and neuroprotective agent as treated group mice took fewer transient cycles to re-entrain after chronic light-dark shift. Neuroprotective property is supported by learning-memory behavioral tests, gene studies and biochemical assays.

Circadian regulation of the immune-hematopoietic system

Earth’s rotation generates the basic circadian rhythm of day and night to which all living organisms must adapt to survive. In mammals, this happens thanks to a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus and to peripheral clock genes at the cellular level. The main environmental cue capable of synchronizing such clocks is light sensed by retinal ganglion cells signaling through a complex nervous pathway to the pineal gland which ultimately regulates melatonin synthesis that occurs during the night, darkness hours in all mammals. The central clock synchronized by melatonin drives the circadian oscillation of the sympathetic nervous system (SNS) adrenergic activity which in turn controls glucocorticoid production in the adrenal glands. These oscillations are integrated with peripheral cellular clocks by still not completely understood mechanisms and drive the homeostatic control of activity-rest (sleep) cycles, cardiovascular activity, body temperature, and immune-hematopoietic functions. The neuronal and hormonal mechanisms governing the circadian oscillation of hematopoiesis and immunity will be addressed in this review focusing on those offering therapeutic perspectives.

1773-P: Glucocorticoid Receptor Signaling Regulates Pancreatic Beta-Cell Circadian Transcriptome and Function

Glucocorticoid (GC) signaling is an important regulator of glucose homeostasis. GC secretion also serves as an entrainment signal that coordinates circadian gene expression of peripheral circadian clocks. Pancreatic beta cells are key biological controllers of glucose homeostasis through the coordinated circadian release of insulin. However, the role of GC signaling in the regulation of beta cell circadian clocks and insulin secretion remains unknown. To address this, we first performed chromatin immunoprecipitation/sequencing (ChIP-seq) in beta cell lines (MIN6 and INS1) and identified >1,000 glucocorticoid receptor (GR)-bound regions (FDR<0.01) in response to the synthetic GC dexamethasone (DEX, 100nM). Annotation of GR-bound regions showed enrichment for pathways regulating insulin secretion and circadian rhythms. To further explore the effects of GC on circadian beta cell gene expression and function in vivo, we used C57BL/6 mice housed under either 12h/12h light-dark cycles (LD) or constant light-mediated circadian disruption (CD). Mice were subsequently administered daily intraperitoneal injections of DEX (2 mg/kg) or vehicle, designed to restore circadian secretion of GC disrupted in CD group. DEX treatment normalized circadian regulation of glucose tolerance (p<0.05 vs. vehicle) and glucose-stimulated insulin secretion (p<0.05 vs vehicle) in CD group. We next utilized RNA sequencing to assess circadian transcriptional profiles in islets isolated from LD, CD, and CD + DEX mice. Consistent with previous studies, CD resulted in abrogation of circadian islet mRNA expression, whereas DEX restored circadian rhythmicity and enhanced expression of core clock genes (e.g., Bmal1, Dbp, Nr1d1) and genes regulating beta cell identity (e.g., Ins1, Nkx6.1) and insulin secretion (e.g., Gck, Irs2). These data highlight the GC/GR axis as a direct regulator of beta cell circadian gene expression, insulin secretion and glucose tolerance. Disclosure S.K.Sen: None. L.Wang: None. M.Brown: None. J.Wu: None. Z.Wei: None. A.Matveyenko: None. Funding National Institutes of Health (DK098468)

Homogalacturonan enriched pectin based hydrogel enhances 6-gingerol's colitis alleviation effect via NF-κB/NLRP3 axis

A nanolipidcarrier (NLC) loaded homogalacturonan enriched pectin (citrus modified pectin, MCP4) hydrogel was designed as a novel colon inflammation site-specific oral delivery system for 6-gingerol (6G) (6G-NLC/MCP4 hydrogel) administration, and its colitis alleviation effect were investigated. 6G-NLC/MCP4 exhibited typical “cage-like” ultrastructure with 6G-NLC embedded in the hydrogel matrix as observed by cryoscanning electron microscope. And due to the homogalacturonan (HG) domain in MCP4 specifically combined with Galectin-3, which is overexpressed in the inflammatory region, the 6G-NLC/MCP4 hydrogel targeted to severe inflammatory region. Meanwhile, the prolonged-release characteristics of 6G-NLC provided sustained release of 6G in severe inflammatory regions. The matrix of hydrogel MCP4 and 6G achieved synergistic alleviation effects for colitis through NF-κB/NLRP3 axis. Specifically, 6G mainly regulated the NF-κB inflammatory pathway and inhibited the activity of NLRP3 protein, while MCP4 regulated the expression of Galectin-3 and peripheral clock gene Rev-Erbα/β to prevent the activation of inflammasome NLRP3.

Desynchronization between Food Intake and Light Stimulations Induces Uterine Clock Quiescence in Female Mice

BackgroundDysmenorrhea is associated with breakfast skipping in young women, suggesting that fasting in the early active phase disrupts uterine functions. ObjectivesTo investigate the possible involvement of the uterine clock system in fasting-induced uterine dysfunction, we examined core clock gene expressions in the uterus using a 28-h interval-fed mouse model. MethodsYoung female mice (8 wk of age) were divided into 3 groups: group I (ad libitum feeding), group II (time-restricted feeding, initial 4 h of the active period every day), and group III (time-restricted feeding for 8 h with a 28-h cycle). Groups II and III have the same fasting interval of 20 h. After analyzing feeding and wheel running behaviors during 2 wk of dietary restriction, mice were sacrificed at 4-h intervals, and the expression profiles of clock genes in the uterus and liver were examined by qPCR. ResultsThe mice in group I took food mainly during the dark phase and those in group II during the initial 4 h of the dark phase, whereas those in group III delayed feeding time by 4 h per cycle. In all groups, spontaneous wheel running was observed during the dark phase. There was no difference in the quantity of feeding and the amount of running exercise among the 3 groups during the second week. The mRNA expressions of peripheral clock genes, Bmal1, Clock, Per1, Per2, Cry1, Nr1d1, and Dbp and a clock-controlled gene, Fabp1, in the uterus showed rhythmic oscillations with normal sequential expression cascade in groups I and II, whereas their expressions decreased and circadian cycles disappeared in group III. In contrast, liver core clock genes in group III showed clear circadian cycles. ConclusionsFluctuations in the timing of the first food intake impair the uterine clock oscillator system to reduce clock gene expressions and abolish their circadian rhythms.

Expression of periferal core molecular clock genes in oral mucosa depends on the chronotype in patients with maxillofacial cellulitis

IntroductionAccurate determination of the patient's chronotype is one of the problems of personalized medicine. Recent studies have shown that determining of the expression of timing genes is a valuable method that can help gain molecular insight into a patient's intrinsic circadian timing. Odontogenic cellulitis is very common pathology. Since acute inflammatory diseases are an urgent pathology, the time of surgical intervention can correspond depend on the time of the patient's hospitalization. Materials and methodsThe level of mRNA expression of peripheral circadian clock genes clock and bmal1, per1, cry1 in buccal epithelial cells in patients with odontogenic purulent inflammatory diseases of maxillofacial area in the morning and evening was investigated. ResultsDuring analyzing the results of the mRNA expression study of the genes of the negative regulatory link of the peripheral molecular clock, per1 and cry1, in patients with Cellulitis of the maxillofacial area, a significant decrease (P = 0.0003) in the mRNA expression level of the cry1 gene by 2.61 times in the evening compared to its morning mRNA expression values. ConclusionThe obtained data indicate that in patients with odontogenic purulent inflammatory diseases of the maxillofacial area with an evening chronotype, a violation of the expression profile of the per1 gene in the cells of the buccal epithelium is noted, which is manifested by an increase in its evening expression in comparison with patients with a morning chronotype.

The Compound Eye Regulates Free-Running Period and Stability of the Circadian Locomotor Rhythm in the Cricket Gryllus bimaculatus.

The circadian system of many multicellular organisms consists of a hierarchical structure of multiple clocks, including central and peripheral clocks. The temporal structure has been analyzed in terms of central-to-peripheral regulation but rarely from the opposite perspective. In this study, the potential control of the central clock in the optic lobe by the peripheral clock in the compound eye was investigated in the cricket Gryllus bimaculatus. The locomotor activity rhythm of crickets in which one of the two bilateral optic lobe clocks was surgically removed was tested in constant darkness at three environmental temperatures (20°C, 25°C, and 30°C) and compared with that of crickets in which the optic nerve connecting between the compound eye and optic lobe of the intact side was also severed. When the optic nerve was severed at 30°C, the free-running period and its stability were significantly increased and decreased, respectively, compared to those of intact and sham-operated crickets, whereas at 20°C, only the free-running period was significantly lengthened, and at 25°C, no significant changes were observed in these parameters. At 30°C, the changes in these two parameters were reproduced when the anterior half of the compound eye was removed, while the removal of the posterior half induced period lengthening only. Together with previous data, these results suggest that the free-running period and stability of the locomotor rhythm are regulated through reciprocal coupling between the clocks in the compound eye and the optic lobe.

Reprogramming of rhythmic liver metabolism by intestinal clock

Temporal oscillations in intestinal nutrient processing and absorption are coordinated by the local clock, which leads to the hypothesis that the intestinal clock has major impacts on shaping peripheral rhythms via diurnal nutritional signals. Here, we investigate the role of the intestinal clock in controlling liver rhythmicity and metabolism. Transcriptomic analysis, metabolomics, metabolic assays, histology, quantitative (q)PCR, and immunoblotting were performed with Bmal1-intestine-specific knockout (iKO), Rev-erba-iKO, and control mice. Bmal1 iKO caused large-scale reprogramming of the rhythmic transcriptome of mouse liver with a limited effect on its clock. In the absence of intestinal Bmal1, the liver clock was resistant to entrainment by inverted feeding and a high-fat diet. Importantly, Bmal1 iKO remodelled diurnal hepatic metabolism by shifting to gluconeogenesis from lipogenesis during the dark phase, leading to elevated glucose production (hyperglycaemia) and insulin insensitivity. Conversely, Rev-erba iKO caused a diversion to lipogenesis from gluconeogenesis during the light phase, resulting in enhanced lipogenesis and an increased susceptibility to alcohol-related liver injury. These temporal diversions were attributed to disruption of hepatic SREBP-1c rhythmicity, which was maintained via gut-derived polyunsaturated fatty acids produced by intestinal FADS1/2 under the control of a local clock. Our findings establish a pivotal role for the intestinal clock in dictating liver rhythmicity and diurnal metabolism, and suggest targeting intestinal rhythms as a new avenue for improving metabolic health. Our findings establish the centrality of the intestinal clock among peripheral tissue clocks, and associate liver-related pathologies with its malfunction. Clock modifiers in the intestine are shown to modulate liver metabolism with improved metabolic parameters. Such knowledge will help clinicians improve the diagnosis and treatment of metabolic diseases by incorporating intestinal circadian factors.