The Expression and Function of Circadian Rhythm Genes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the most common and lethal form of cancer worldwide. However, its diagnosis and treatment are still dissatisfactory, due to limitations in the understanding of its pathogenic mechanism. Therefore, it is important to elucidate the molecular mechanisms and identify novel therapeutic targets for HCC. Circadian rhythm-related genes control a variety of biological processes. These genes play pivotal roles in the initiation and progression of HCC and are potential diagnostic markers and therapeutic targets. This review gives an update on the research progress of circadian rhythms, their effects on the initiation, progression, and prognosis of HCC, in a bid to provide new insights for the research and treatment of HCC.

Melatonin mediates monochromatic light-induced proliferation of T/B lymphocytes in the spleen via the membrane receptor or nuclear receptor.

Our studies found that melatonin mediates the monochromatic light-induced lymphocyte proliferation in chickens. However, melatonin receptor subtypes contain membrane receptor (Mel1a/Mel1b/Mel1c) and nuclear receptor (Retinoic acid receptor-related orphan receptor [ROR] α/RORß/RORγ) and are characteristic with cell specificity. This study compared receptor pathway of melatonin, which mediated the monochromatic light-induced T/B lymphocyte proliferations in chickens. Newly hatched chicks were randomly divided into white light, red light, green light (GL), and blue light groups. Green light promoted the membrane receptor expression in the spleen but decreased the nuclear receptor level compared with that of red light. These changes were accompanied by increase of T/B lymphocyte proliferation and plasma melatonin level under GL. Pinealectomy reversed aforementioned changes and resulted in no differences among the light-treated groups. Supplementation of exogenous melatonin enhanced GL-induced T/B lymphocyte proliferation in the spleen but was reversed by Mel1c antagonist prazosin and RORα agonist SR1078 and enhanced by RORα antagonist SR3335. However, Mel1b antagonist 4P-PDOT and RORγ antagonist GSK increased the stimulation effect of melatonin on GL-induced T lymphocyte proliferation but no effect on the B-lymphocyte proliferation. These results indicate that melatonin promotes the GL-induced T lymphocyte proliferation through Mel1b, Mel1c, and RORα/RORγ; however, the Mel1a, Mel1c, and RORα may be involved in the B lymphocyte proliferation.

Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease.

Circadian clock proteins are endogenous timing mechanisms that control the transcription of hundreds of genes. Their integral role in coordinating metabolism has led to their scrutiny in a number of diseases, including nonalcoholic fatty liver disease (NAFLD). Discoordination between central and peripheral circadian rhythms is a core feature of nearly every genetic, dietary, or environmental model of metabolic syndrome and NAFLD. Restricting feeding to a defined daily interval (time-restricted feeding) can synchronize the central and peripheral circadian rhythms, which in turn can prevent or even treat the metabolic syndrome and hepatic steatosis. Importantly, a number of proteins currently under study as drug targets in NAFLD (sterol regulatory element-binding protein [SREBP], acetyl-CoA carboxylase [ACC], peroxisome proliferator-activator receptors [PPARs], and incretins) are modulated by circadian proteins. Thus, the clock can be used to maximize the benefits and minimize the adverse effects of pharmaceutical agents for NAFLD. The circadian clock itself has the potential for use as a target for the treatment of NAFLD.

Supply of methionine and arginine alters phosphorylation of mechanistic target of rapamycin (mTOR), circadian clock proteins, and α-s1-casein abundance in bovine mammary epithelial cells.

Methionine (Met) and arginine (Arg) regulate casein protein abundance through alterations in activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. A potential role for the circadian clock network on the regulation of protein synthesis, partly via activity of mTORC1, has been highlighted in non-ruminants. The main objective of the study was to determine in ruminant mammary cells alterations in mRNA, protein abundance and phosphorylation status of mTORC1-related upstream targets, circadian clock proteins, and protein kinase AMP-activated catalytic subunit alpha (AMPK) in relation to α-s1-casein protein (CSN1S1) abundance in response to greater supply of Met and Arg alone or in combination. Primary bovine mammary epithelial cells (BMEC) were incubated for 12 h in a 2 × 2 arrangement of treatments with control media (ideal profile of amino acids, IPAA), or media supplemented with increased Met (incMet), Arg (incArg), or both (incMet + incArg). Data were analyzed testing the main effects of Met and Arg and their interaction. Among 7 amino acid (AA) transporters known to be mTORC1 targets, increasing supply of Arg downregulated SLC1A5, SLC3A2, SLC7A1, and SLC7A5, while increasing supply of Met upregulated SLC7A1. mRNA abundance of the cytosolic Arg sensor (CASTOR1) was lower when supply of Arg and Met alone increased. p-TSC2 (TSC complex subunit 2) was greater when the Arg supply was increased, while the phosphoralation ratio of p-AKT (AKT serine/threonine kinase 1):total (t) AKT and p-AMPK:tAMPK were lower. In spite of this, the ratio of p-mTOR:tmTOR nearly doubled with incArg but such response did not prevent a decrease in CSN1S1 abundance. The abundance of period circadian regulator 1 (PER1) protein nearly doubled with all treatments, but only incMet + incArg led to greater clock circadian regulator (CLOCK) protein abundance. Overall, data suggest that a greater supply of Met and Arg could influence CSN1S1 synthesis of BMEC through changes in the mTORC1, circadian clock, and AMPK pathways. Identifying mechanistic relationships between intracellular energy, total AA supply, and these pathways in the context of milk protein synthesis in ruminants merits further research.

An Application of the Bayesian Periodicity Test to Identify Diurnal Rhythm Genes in the Brain.

Biological systems are extremely dynamic and many aspects of cellular processes show rhythmic circadian patterns. Extracting such information from large expression data is challenging. In this work, we present a modified application of the Empirical Bayes periodicity test to identify genes with diurnal rhythmic behavior in two brain regions. The hypothalamus and amygdala gene expression data were generated from 100 BXD recombinant inbred mice during the day hours. Brain samples were collected over the course of two days. We first filtered the transcripts based on rank correlation at matched time points between day-1 and day-2. We then applied the proposed test of periodicity to identify diurnal rhythm genes in the full cohort and gender-specific sub-cohorts. In hypothalamus, at a Benjamini-Hochberg false discovery rate (BH-FDR) of 0.01, we identified 15 transcripts with cyclic behavior in the full cohort, none, and 53 transcripts in the female and male cohort, respectively. Similarly, in amygdala, we identified 58 diurnal rhythm genes in the full cohort, and 1 and 28 in the female and male cohorts, respectively. In conclusion, we present a modified version of the empirical Bayes periodicity test to detect periodic expression patterns. Our results demonstrate that this approach can capture cyclic patterns from relatively noisy expression data sets.

A single factor dominates the behavior of rhythmic genes in mouse organs.

BACKGROUND: Circadian rhythm, regulated by both internal and external environment of the body, is a multi-scale biological oscillator of great complexity. On the molecular level, thousands of genes exhibit rhythmic transcription, which is both organ- and species-specific, but it remains a mystery whether some common factors could potentially explain their rhythmicity in different organs. In this study we address this question by analyzing the transcriptome data in 12 mouse organs to determine such major impacting factors. RESULTS: We found a strong positive correlation between the transcriptional level and rhythmic amplitude of circadian rhythmic genes in mouse organs. Further, transcriptional level could explain over 70% of the variation in amplitude. In addition, the functionality and tissue specificity were not strong predictors of amplitude, and the expression level of rhythmic genes was linked to the energy consumption associated with transcription. CONCLUSION: Expression level is a single major factor impacts the behavior of rhythmic genes in mouse organs. This single determinant implicates the importance of rhythmic expression itself on the design of the transcriptional system. So, rhythmic regulation of highly expressed genes can effectively reduce the energetic cost of transcription, facilitating the long-term adaptive evolution of the entire genetic system.

Diurnal Regulation of the Orexin/Hypocretin System in Mice.

A prominent feature of the hypothalamic neuropeptides orexins/hypocretins is their role in the regulation of sleep-wake behavior. While there is strong evidence for a diurnal (i.e. 24-h) rhythmicity of the expression of prepro-orexin (PPO) and its cleavage products, orexin A and B, it is not known whether orexin receptors are also subject to diurnal regulation. Here we ask whether besides the regulation of PPO the expression of the orexin receptor subtypes OX1R and OX2R varies over 24 hours in the mouse brain. The mRNA levels of PPO, OX1R, and OX2R as well as of various clock genes were analyzed over 24 hours in the hypothalamus, cortex, and adrenal glands of male mice using qPCR. We found a significant diurnal regulation of the mRNA levels of PPO as well as both orexin receptor subtypes in the brain, while no regulation was observed in adrenal glands. While in the cortex the mRNA levels of both OX1R and OX2R showed a significant diurnal regulation, in the hypothalamus, only the OX2R mRNA expression was subject to a diurnal rhythm. The expression of both orexin receptor subtypes significantly correlated with that of clock genes. Remarkably, the expression pattern of OX2R showed a strong and highly significant correlation with that of the clock gene Bmal1 in the cortex and hypothalamus. These results suggest that the rhythmic expression of orexin receptors is linked to clock gene expression and that OX2R may potentially play a role in the timing of sleep-wake behavior.

Circadian rhythms: a regulator of gastrointestinal health and dysfunction.

INTRODUCTION: Circadian rhythms regulate much of gastrointestinal physiology including cell proliferation, motility, digestion, absorption, and electrolyte balance. Disruption of circadian rhythms can have adverse consequences including the promotion of and/or exacerbation of a wide variety of gastrointestinal disorders and diseases. Areas covered: In this review, we evaluate some of the many gastrointestinal functions that are regulated by circadian rhythms and how dysregulation of these functions may contribute to disease. This review also discusses some common gastrointestinal disorders that are known to be influenced by circadian rhythms as well as speculation about the mechanisms by which circadian rhythm disruption promotes dysfunction and disease pathogenesis. We discuss how knowledge of circadian rhythms and the advent of chrono-nutrition, chrono-pharmacology, and chrono-therapeutics might influence clinical practice. Expert opinion: As our knowledge of circadian biology increases, it may be possible to incorporate strategies that take advantage of circadian rhythms and chronotherapy to prevent and/or treat disease.

Circadian-Regulated Cell Death in Cardiovascular Diseases.

BACKGROUND: Over the past several years, a variety of human and animal studies have shown that circadian clocks regulate biological cardiovascular rhythms in both health and disease. For example, heart rate and blood pressure fluctuate over 24-hour daily periods, such that levels are higher in the morning and progressively decline in the evening. METHODS AND RESULTS: It is interesting to note that the timing of the administration of various cardiac treatments can also benefit some cardiovascular outcomes. Circadian rhythms have been implicated in the pathogenesis of a number of cardiovascular diseases, including myocardial infarction, ischemia-reperfusion injury after myocardial infarction, and heart failure. Cell death is a major component of ischemia-reperfusion injury and posited as the central underlying cause of ventricular remodeling and cardiac dysfunction following myocardial infarction. It is notable that the time of day profoundly influences cardiac tolerance and sensitivity to cardiac injury. CONCLUSIONS: Herein, we highlight the novel relationship between circadian rhythms and homeostatic processes that governs cell fate by apoptosis, necrosis, and autophagy. Understanding how these intricate processes interconnect at the cellular level is of paramount clinical importance for optimizing treatment strategies to achieve maximum cardiovascular outcome.

The tumour suppressing role of the circadian clock.

The circadian clock and the ~24 h rhythms it generates are essential in maintaining regular tissue functioning. At the molecular level, the circadian clock comprises a core set of rhythmically expressed genes and gene products that are able to drive rhythmic expression of other genes to generate overt circadian rhythms. It has recently come to light that perturbations of circadian rhythms contribute to the development of pathological states such as cancer, and altered expression and/or regulation of circadian clock genes has been identified in multiple tumour types. This review summarises the important role the circadian system plays in regulating cellular processes, including the cell cycle, apoptosis, DNA repair, the epithelial-to-mesenchymal transition, metabolism and immunity and how its dysregulation has widespread implications and could be a critical player in the development of cancer. Understanding its role in cancer development is important for the field chronotherapy, where the timing of chemotherapy administration is optimised based on differences in circadian clock functioning in normal and cancer cells. This has been found to influence the patient response, minimising the side effects commonly associated with chemotherapy. © 2019 IUBMB Life, 2019.

Daily expression of clock genes in central and peripheral tissues of tree sparrow (Passer montanus).

Almost all organisms live in a fluctuating environment. To achieve synchrony with the fluctuating environment, organisms have evolved with time-tracking mechanism commonly known as biological clocks. This circadian clock machinery has been identified in almost all cells of vertebrates and categorized as central and peripheral clocks. In birds, three independent circadian clocks reside within the nervous tissues in the hypothalamus, pineal and retina, which interact with each other and produce circadian time at a functional level. There is limited knowledge available of the molecular clockwork, and of integration between central and peripheral clocks in birds. Here, we studied daily expression of canonical clock genes (Bmal1, Clock, Per2, Per3, Cry1 and Cry2) and clock-controlled gene (Npas2) in all three central tissues (hypothalamus, pineal and retina) and in peripheral tissues (liver, intestine and muscle). Wild caught adult male tree sparrows were exposed to equinox photoperiod (12L:12D) for 2 weeks and after that birds were sacrificed (N = 5 per time point) at six time points (ZT1, ZT5, ZT9, ZT13, ZT17 and ZT21; ZT0 is lights on). Daily expression of clock genes was studied using qPCR. Bmal1, Clock, Per2, Per3, Cry1, Cry2 and Npas2 showed daily oscillation in all tissues except Cry2 in hypothalamus, pineal and intestine. We observed tissue-specific expression pattern for all clock and clock-controlled genes. Bmal1 transcripts expressed during early phase of night. Clock acrophase was observed during middle or late day time in the central clock while during early-to-middle phase of night in peripheral tissues. Npas2 expression pattern was similar to Bmal1. Per genes peaked either late at night or early during day time. However, Cry genes were peaked either at late day time (Cry1in retina, liver and intestine; Cry2 in liver and intestine) or at early night phase (Cry1 in hypothalamus, pineal and muscle; Cry2 in hypothalamus, pineal, retina and muscle). Our results are consistent with the autoregulatory circadian feedback loop, and suggest a conserved tissue-level circadian time generation in tree sparrows. Change in peak expression timing of these genes in different tissues implicates tissue-specific contribution of individual clock genes in the circadian time generation.

Ursolic Acid Attenuates Hepatic Steatosis, Fibrosis, and Insulin Resistance by Modulating the Circadian Rhythm Pathway in Diet-Induced Obese Mice.

The aim of the current study was to elucidate the effects of long-term supplementation with dietary ursolic acid (UR) on obesity and associated comorbidities by analyzing transcriptional and metabolic responses, focusing on the role of UR in the modulation of the circadian rhythm pathway in particular. C57BL/6J mice were divided into three groups and fed a normal diet, high-fat diet, or high-fat + 0.05% (w/w) UR diet for 16 weeks. Oligonucleotide microarray profiling revealed that UR is an effective regulator of the liver transcriptome, and canonical pathways associated with the "circadian rhythm" and "extracellular matrix (ECM)⁻receptor interactions" were effectively regulated by UR in the liver. UR altered the expression of various clock and clock-controlled genes (CCGs), which may be linked to the improvement of hepatic steatosis and fibrosis via lipid metabolism control and detoxification enhancement. UR reduced excessive reactive oxygen species production, adipokine/cytokine dysregulation, and ECM accumulation in the liver, which also contributed to improve hepatic lipotoxicity and fibrosis. Moreover, UR improved pancreatic islet dysfunction, and suppressed hepatic gluconeogenesis, thereby reducing obesity-associated insulin resistance. Therapeutic approaches targeting hepatic circadian clock and CCGs using UR may ameliorate the deleterious effects of diet-induced obesity and associated complications such as hepatic fibrosis.

Involvement of cortisol and sirtuin1 during the response to stress of hypothalamic circadian system and food intake-related peptides in rainbow trout, Oncorhynchus mykiss.

Stress is conditioning animal welfare by negatively affecting a wide range of physiological and behavioral functions. This may be applied to circadian physiology and food intake. Cortisol, the stress-related hormone, may mediate such effect of stress, but other indirect mediators might be considered, such as sirtuin1. Then, either the independent modulatory effect or the existence of any interaction between mediators may be responsible. The circadian system is the main modulator of several integrative mechanisms at both central and peripheral levels that are rhythmically presented, thus influencing different processes such as food intake. In this way, food intake is controlled by the circadian system, as demonstrated by the persistence of such rhythms of food intake in the absence of environmental external cues. Our study aimed to evaluate the daily profile of hypothalamic mRNA abundance of circadian clock genes (clock1a, bmal1, per1 and rev-erbß-like), and food intake regulators (crf, pomc-a1, cart, and npy) in rainbow trout (Oncorhynchus mykiss), the impact of stress on such rhythms, and the involvement of cortisol and sirtuin1 as mediators. Four cohorts of trout were subjected to 1) normal stocking density (control group), 2) high stocking density for 72 hours (stress group), 3) normal stocking density and implanted with mifepristone, a glucocorticoid receptors antagonist, and 4) mifepristone administered and stressed for 72 hours. Fish from each group were sampled every 4-h along the 24-h LD cycle, and cortisol, glucose and lactate plasma levels were evaluated. Hypothalamic mRNA abundance of clock genes, food intake regulators, glucocorticoid receptors and sirtuin1 were qPCR assayed. Our results reveal the impact of stress on most of the genes assayed, but different mechanisms appear to be involved. The rhythm of clock genes displayed decreased amplitude and averaged levels in stressed trout, with no changes of the acrophase being observed. This effect was not prevented by mifepristone. On the contrary, the effect of stress on the daily profile of crf, pomc-a1, and npy was totally prevented by mifepristone administration. Accordingly, cortisol appears to mainly mediate the effect of stress on food intake regulators through binding to specific glucocorticoid receptors within trout hypothalamus, whereas sirtuin1 is apparently mediating such effects on the circadian system in the same brain region. Further research must be performed to clarify those mechanisms through which stress influences food intake and the circadian oscillator within the same brain region, hypothalamus, in rainbow trout, and the interaction among them all.

Vasculature on the clock: Circadian rhythm and vascular dysfunction.

The master mammalian circadian clock (i.e. central clock), located in the suprachiasmatic nucleus of the hypothalamus, orchestrates the synchronization of the daily behavioural and physiological rhythms to better adapt the organism to the external environment in an anticipatory manner. This central clock is entrained by a variety of signals, the best established being light and food. However, circadian cycles are not simply the consequences of these two cues but are generated by endogenous circadian clocks. Indeed, clock machinery is found in mainly all tissues and cell types, including cells of the vascular system such as endothelial cells, fibroblasts, smooth muscle cells and stem cells. This machinery physiologically contributes to modulate the daily vascular function, and its disturbance therefore plays a major role in the pathophysiology of vascular dysfunction. Therapies targeting the circadian rhythm may therefore be of benefit against vascular disease.

Temporal expression of clock genes in central and peripheral tissues of spotted munia under varying light conditions: Evidence for circadian regulation of daily physiology in a non-photoperiodic circannual songbird species.

We investigated if the duration and/or frequency of the light period affect 24-h rhythm of circadian clock genes in central and peripheral tissues of a non-photoperiodic songbird, the spotted munia (Lonchura punctulata), in which a circannual rhythm regulates the reproductive cycle. We monitored activity-rest pattern and measured 24-h mRNA oscillation of core clock (Bmal1, Clock, Per2, Cry1 and Cry2) and clock-controlled (E4bp4, Rorα and Rev-erbα) genes in the hypothalamus, retina, liver and gut of spotted munia subjected to an aberrant light-dark (LD) cycle (3.5L:3.5D; T7, T = period length of LD cycle) and continuous light (LL, 24L:0D), with controls on 24-h LD cycle (T24, 12L:12D). Munia exhibited rhythmic activity-rest pattern with period matched to T7 or T24 under an LD cycle and were arrhythmic with a scattered activity pattern and higher activity duration under LL. At the transcriptional level, both clock and clock-controlled genes showed a significant 24-h rhythm in all four tissues (except Clock in the liver) under 12L:12D, suggesting a conserved tissue-level circadian time generation in spotted munia. An exposure to 3.5L:3.5D or LL induced arrhythmicity in transcriptional oscillation of all eight genes in the hypothalamus (except Rev-erbα) and liver (except Bmal1 and Rev-erbα under T7 and Cry1 under LL). In the retina, however, all genes showed arrhythmic 24-h mRNA expression under LL, but not under T7 (except in E4bp4 and Rorα). Interestingly, unlike in the liver, Bmal1, Per2, Cry1, Rorα and Rev-erbα mRNA expressions were rhythmic in the gut under both T7 (except Rorα) and LL conditions. These results showed variable relationship of internal circadian clocks with the external light environment and suggested a weak coupling of circadian clocks between the central (hypothalamus and retina) and peripheral (liver and gut) tissues. We suggest tissue-level circadian clock regulation of daily physiology and behavior in the spotted munia.

Gut Microbiota-Derived Short Chain Fatty Acids Induce Circadian Clock Entrainment in Mouse Peripheral Tissue.

Microbiota-derived short-chain fatty acids (SCFAs) and organic acids produced by the fermentation of non-digestible fibre can communicate from the microbiome to host tissues and modulate homeostasis in mammals. The microbiome has circadian rhythmicity and helps the host circadian clock function. We investigated the effect of SCFA or fibre-containing diets on circadian clock phase adjustment in mouse peripheral tissues (liver, kidney, and submandibular gland). Initially, caecal SCFA concentrations, particularly acetate and butyrate, induced significant day-night differences at high concentrations during the active period, which were correlated with lower caecal pH. By monitoring luciferase activity correlated with the clock gene Period2 in vivo, we found that oral administration of mixed SCFA (acetate, butyrate, and propionate) and an organic acid (lactate), or single administration of each SCFA or lactate for three days, caused phase changes in the peripheral clocks with stimulation timing dependency. However, this effect was not detected in cultured fibroblasts or cultured liver slices with SCFA applied to the culture medium, suggesting SCFA-induced indirect modulation of circadian clocks in vivo. Finally, cellobiose-containing diets facilitated SCFA production and refeeding-induced peripheral clock entrainment. SCFA oral gavage and prebiotic supplementation can facilitate peripheral clock adjustment, suggesting prebiotics as novel therapeutic candidates for misalignment.

Circadian regulation of auditory function.

The circadian system integrates environmental cues to regulate physiological functions in a temporal fashion. The suprachiasmatic nucleus, located in the hypothalamus, is the master clock that synchronizes central and peripheral organ clocks to orchestrate physiological functions. Recently, molecular clock machinery has been identified in the cochlea unravelling the potential involvement in the circadian regulation of auditory functions. Here, we present background information on the circadian system and review the recent findings that introduce circadian rhythms to the auditory field. Understanding the mechanisms by which circadian rhythms regulate auditory function will provide fundamental knowledge on the signalling networks that control vulnerability and resilience to auditory insults.

High-Throughput Sequencing Reveals Hypothalamic MicroRNAs as Novel Partners Involved in Timing the Rapid Development of Chicken (Gallus gallus) Gonads.

Onset of the rapid gonad growth is a milestone in sexual development that comprises many genes and regulatory factors. The observations in model organisms and mammals including humans have shown a potential link between miRNAs and development timing. To determine whether miRNAs play roles in this process in the chicken (Gallus gallus), the Solexa deep sequencing was performed to analyze the profiles of miRNA expression in the hypothalamus of hens from two different pubertal stages, before onset of the rapid gonad development (BO) and after onset of the rapid gonad development (AO). 374 conserved and 46 novel miRNAs were identified as hypothalamus-expressed miRNAs in the chicken. 144 conserved miRNAs were showed to be differentially expressed (reads > 10, P < 0.05) during the transition from BO to AO. Five differentially expressed miRNAs were validated by real-time quantitative RT-PCR (qRT-PCR) method. 2013 putative genes were predicted as the targets of the 15 most differentially expressed miRNAs (fold-change > 4.0, P < 0.01). Of these genes, 7 putative circadian clock genes, Per2, Bmal1/2, Clock, Cry1/2, and Star were found to be targeted multiple times by the miRNAs. qRT-PCR revealed the basic transcription levels of these clock genes were much higher (P < 0.01) in AO than in BO. Further functional analysis suggested that these 15 miRNAs play important roles in transcriptional regulation and signal transduction pathways. The results provide new insights into miRNAs functions in timing the rapid development of chicken gonads. Considering the characteristics of miRNA functional conservation, the results will contribute to the research on puberty onset in humans.

Neonatal capsaicin treatment in rats affects TRPV1-related noxious heat sensation and circadian body temperature rhythm.

The transient receptor potential vanilloid 1 (TRPV1) is a cation channel that serves as a polymodal detector of noxious stimuli such as capsaicin. Therefore, capsaicin treatment has been used to investigate the physiological function of TRPV1. Here, we report physiological changes induced by treating neonatal rats with capsaicin. Capsaicin (50mg/kg) (cap-treated) or vehicle (vehicle-treated) was systemically administered to newborn SD rat pups within 48 h after birth. TRPV1 expression, intake volume of capsaicin water, and noxious heat sensation were measured 6 weeks after capsaicin treatment. Circadian body temperature and locomotion were recorded by biotelemetry. Expression of Per1, Per2, Bmal1 and Hsf1 (clock genes) was also investigated. Neonatal capsaicin treatment not only decreased TRPV1 expression but also induced desensitization to noxious heat stimuli. Circadian body temperature of cap-treated rats increased significantly compared with that of vehicle-treated rats. Additionally, the amplitude of the circadian body temperature was reversed in cap-treated rats. Expression of the hypothalamic Hsf1 and liver Per2 clock genes followed a similar trend. Therefore, we suggest that these findings will be useful in studying various physiological mechanisms related to TRPV1.