Resveratrol Induces Myotube Development by Altering Circadian Metabolism via the SIRT1-AMPK-PP2A Axis.

Resveratrol is a polyphenol known to have metabolic as well as circadian effects. However, there is little information regarding the metabolic and circadian effect of resveratrol on muscle cells. We sought to investigate the metabolic impact of resveratrol throughout the circadian cycle to clarify the associated signaling pathways. C2C12 myotubes were incubated with resveratrol in the presence of increasing concentrations of glucose, and metabolic and clock proteins were measured for 24 h. Resveratrol led to SIRT1, AMPK and PP2A activation. Myotubes treated with increasing glucose concentrations showed higher activation of the mTOR signaling pathway. However, resveratrol did not activate the mTOR signaling pathway, except for P70S6K and S6. In accordance with the reduced mTOR activity, resveratrol led to advanced circadian rhythms and reduced levels of pBMAL1 and CRY1. Resveratrol increased myogenin expression and advanced its rhythms. In conclusion, resveratrol activates the SIRT1-AMPK-PP2A axis, advances circadian rhythms and induces muscle development.

ß-Hydroxy-ß-methylbutyrate (HMB) leads to phospholipase D2 (PLD2) activation and alters circadian rhythms in myotubes.

ß-Hydroxy-ß-methylbutyrate (HMB) is a breakdown product of leucine, which promotes muscle growth. Although some studies indicate that HMB activates AKT and mTOR, others show activation of the downstream effectors, P70S6K and S6, independent of mTOR. Our aim was to study the metabolic effect of HMB around the circadian clock in order to determine more accurately the signaling pathway involved. C2C12 myotubes were treated with HMB and clock, metabolic and myogenic markers were measured around the clock. HMB-treated C2C12 myotubes showed no activation of AKT and mTOR, but did show activation of P70S6K and S6. Activation of P70S6K and S6 was also found when myotubes were treated with HMB combined with metformin, an indirect mTOR inhibitor, or rapamycin, a direct mTOR inhibitor. The activation of the P70S6K and S6 independent of AKT and mTOR, was accompanied by increased activation of phospholipase D2 (PLD). In addition, HMB led to high amplitude and advanced circadian rhythms. In conclusion, HMB induces myogenesis in C2C12 by activating P70S6K and S6 via PLD2, rather than AKT and mTOR, leading to high amplitude advanced rhythms.

Mucosal Genes Encoding Clock, Inflammation and Their Mutual Regulators Are Disrupted in Pediatric Patients with Active Ulcerative Colitis.

Patients with active ulcerative colitis (UC) display a misalignment of the circadian clock, which plays a vital role in various immune functions. Our aim was to characterize the expression of clock and inflammation genes, and their mutual regulatory genes in treatment-naïve pediatric patients with UC. Using the Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) platform and R algorithms, we analyzed rectal biopsy transcriptomic data from two cohorts (206 patients with UC vs. 20 healthy controls from the GSE-109142 study, and 43 patients with UC vs. 55 healthy controls from the GSE-117993 study). We compared gene expression levels and correlation of clock genes (BMAL1, CLOCK, PER1, PER2, CRY1, CRY2), inflammatory genes (IκB, IL10, NFκB1, NFκB2, IL6, TNFα) and their mutual regulatory genes (RORα, RORγ, REV-ERBα, PGC1α, PPARα, PPARγ, AMPK, SIRT1) in patients with active UC and healthy controls. The clock genes BMAL1, CLOCK, PER1 and CRY1 and the inflammatory genes IκB, IL10, NFκB1, NFκB2, IL6 and TNFα were significantly upregulated in patients with active UC. The genes encoding the mutual regulators RORα, RORγ, PGC1α, PPARα and PPARγ were significantly downregulated in patients with UC. A uniform pattern of gene expression was found in healthy controls compared to the highly variable expression pattern in patients with UC. Among the healthy controls, inflammatory genes were positively correlated with clock genes and they all showed reduced expression. The difference in gene expression levels was associated with disease severity and endoscopic score but not with histological score. In patients with active UC, clock gene disruption is associated with abnormal mucosal immune response. Disrupted expression of genes encoding clock, inflammation and their mutual regulators together may play a role in active UC.

Effect of early vs. late time-restricted high-fat feeding on circadian metabolism and weight loss in obese mice.

Time-restricted feeding (TRF) limits the time and duration of food availability without calorie reduction. Although a high-fat (HF) diet leads to disrupted circadian rhythms, TRF can prevent metabolic diseases, emphasizing the importance of the timing component. However, the question of when to implement the feeding window and its metabolic effect remains unclear, specifically in obese and metabolically impaired animals. Our aim was to study the effect of early vs. late TRF-HF on diet-induced obese mice in an 8:16 light-dark cycle. C57BL male mice were fed ad libitum a high-fat diet for 14 weeks after which they were given the same food during the early (E-TRF-HF) or late (L-TRF-HF) 8 h of the dark phase for 5 weeks. The control groups were fed ad libitum either a high-fat (AL-HF) or a low-fat diet (AL-LF). Respiratory exchange ratio (RER) was highest for the AL-LF group and the lowest for the AL-HF group. E-TRF-HF led to lower body weight and fat depots, lower glucose, C-peptide, insulin, cholesterol, leptin, TNFα, and ALT levels compared with L-TRF-HF- and AL-HF-fed mice. TRF-HF regardless whether it was early or late led to reduced inflammation and fat accumulation compared with AL-HF-fed mice. E-TRF-HF led to advanced liver circadian rhythms with higher amplitudes and daily expression levels of clock proteins. In addition, TRF-HF led to improved metabolic state in muscle and adipose tissue. In summary, E-TRF-HF leads to increased insulin sensitivity and fat oxidation and decreased body weight, fat profile and inflammation contrary to AL-HF-fed, but comparable to AL-LF-fed mice. These results emphasize the importance of timed feeding compared to ad libitum feeding, specifically to the early hours of the activity period.

Differential Effect of Fructose in the Presence or Absence of Fatty Acids on Circadian Metabolism in Hepatocytes.

We aimed to explore whether fructose in the absence or presence of fatty acids modulates circadian metabolism in AML-12 hepatocytes. Fructose treatment under steatosis conditions (FruFA) led to fat synthesis resulting in increased triglycerides and cholesterol content. Fructose led to reduced activity of the AMPK and mTOR-signaling pathway. However, FruFA treatment led to inhibition of the AMPK signaling pathway but activation of the mTOR pathway. Fructose also increased the expression of inflammatory markers, whereas the addition of fatty acids dampened their circadian expression. At the clock level, fructose or FruFA altered the expression of the core clock. More specifically, fructose led to altered expression of the BMAL1-RORα-REV-ERBα axis, together with reduced phosphorylated BMAL1 levels. In conclusion, our results show that hepatocytes treated with fructose respond differently if fatty acids are present, leading to a differential effect on metabolism and circadian rhythms. This is achieved by modulating BMAL1 activity and expression.

Relationship among chrononutrition, sleep, and glycemic control in women with gestational diabetes mellitus: a randomized controlled trial.

BACKGROUND: Gestational diabetes mellitus is associated with an increased risk of maternal, fetal, and neonatal morbidities. Chronobiological disorders have recently been identified as risk factors for those morbidities. The disorders include chrononutritional disorders related to meal frequency and content according to the sleep-wake cycle, sleep disorders related to sleep quality, and chrono-obesity disorders, such as abnormal weight gain because of sleep deprivation and time of eating. OBJECTIVE: This study aimed to assess whether a chrononutritional and sleep hygiene intervention can improve maternal glycemic control and reduce the proportion of large-for-gestational-age newborns among women with gestational diabetes mellitus. STUDY DESIGN: This randomized controlled trial included 103 women with gestational diabetes mellitus who were carrying a singleton fetus and assigned to either the intervention group (n=33) or the control group (n=70). The intervention group was assigned to a chrononutrition and sleep hygiene program, in addition to the usual care for gestational diabetes mellitus, from the time of diabetes mellitus diagnosis to birth, whereas the control group received the usual gestational diabetes mellitus care. RESULTS: The chrononutritional and sleep hygiene intervention significantly reduced the proportion of women with suboptimal glycemic control (<80% of the plasma glucose values at target), after adjustment for maternal age, prepregnancy body mass index, gravidity, history of gestational diabetes mellitus, and large for gestational age (relative risk, 0.28; 95% confidence interval, 0.18-0.81). The effect of the intervention on balancing maternal glycemic control was mainly because of the decreased carbohydrate intake in the evening interval of the day (relative risk, 0.8; 95% confidence interval, 0.64-0.99). However, the intervention had no effect on the proportion of large-for-gestational-age newborns. CONCLUSION: The chrononutritional and sleep hygiene intervention can improve maternal glycemic control.

Resveratrol Induces the Fasting State and Alters Circadian Metabolism in Hepatocytes.

Resveratrol is a nutritional substance that has both metabolic and circadian effects. While some studies indicate a correlation between resveratrol and reduced gluconeogenesis, others propose the opposite. Our aim was to study the metabolic effect of resveratrol around the circadian clock in order to determine more accurately the hepatic signaling pathways involved. AML-12 hepatocytes were treated with resveratrol and clock and metabolic markers were measured around the clock. Resveratrol-treated AML-12 hepatocytes showed reduced ratio of the following key metabolic factors: phosphorylated PP2A to total PP2A (pPP2A/PP2A), pAKT/AKT, pFOXO1/FOXO1 and pAMPK/AMPK, indicating inhibition of AKT and AMPK, but activation of PP2A and FOXO1. In addition, the levels of phosphorylated mTOR were low after resveratrol treatment. The levels of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) were significantly higher after resveratrol treatment. In accordance with the reduced mTOR activity, the ratio of pBMAL1/BMAL1, the clock transcription factor, also decreased. Bmal1 mRNA oscillated robustly in AML-12 hepatocytes, but resveratrol treatment led to a phase advance and a decrease in its amplitude, similarly to the effect on Srebp1c and Pgc1α mRNA. After resveratrol treatment, daily mRNA levels of Bmal1, Sirt1 and Srebp1c were significantly higher. Resveratrol changes the circadian expression of metabolic and clock genes activating the fasting state and inducing the PP2A-FOXO1-PEPCK pathway.

Time-Restricted Feeding in Commercial Layer Chickens Improves Egg Quality in Old Age and Points to Lack of Adipostat Activity in Chickens.

In mammals, time-restricted feeding (TRF) with no caloric restriction provides health benefits and extends longevity, usually with a minor (∼3%) or no reduction in total food consumption. In the current study, a TRF regimen of 6 h free access to food (08:00-14:00 h) was applied to Leghorn chickens from 25 to 86 weeks of age; control birds ate freely during the light hours (06:00-20:00 h). Unexpectedly, the TRF-treated birds consumed, on average, 11.7% less food than the controls. This was manifested by an average reduction of 9.6% in body weight, 2.6-fold in visceral fat accumulation, and 6.5% in egg weight. Hen-housed egg production was reduced by 3.6% in the TRF group compared with the control, along the first 40 weeks of the follow-up (P < 0.05), and changed into a tendency of 0.7% higher egg production thereafter. Several parameters of egg quality showed significant improvement (P < 0.05) in the TRF group compared with the controls. A comparison of diurnal patterns of feed consumption revealed a higher rate of hourly consumption in the TRF group and increased consumption before dark in the control group. In conclusion, the reduced feed intake in response to the TRF treatment and loss in visceral fat accumulation supports the lack of a strong adipostat activity in chickens and different appetite regulation mechanisms compared with mammals. Therefore, future TRF studies in chickens should be adjusted by extending the ad libitum time window. The lower feed intake by the TRF-treated chickens compared with the ad libitum-fed controls seems to reduce the efficiency of egg production. Nevertheless, the improved egg quality and persistence of egg lay at the older age suggest that similarly to mammals, the TRF treatment delayed at least some of the negative impacts associated with advanced age.

Serum from type 2 diabetes patients consuming a three-meal diet resets circadian rhythms in cultured hepatocytes.

AIMS: Feeding regimens alter circadian rhythms in peripheral tissues, but the mechanism is not understood. We aimed to study whether soluble factors, rather than neuronal-based communication, directly influence circadian rhythms in the liver, in response to a nutritional treatment in type 2 diabetes (T2D) patients. METHODS: Cultured hepatocytes were treated with serum of insulin-treated T2D patients following either a three-meal diet (3Mdiet) or six-meal diet (6Mdiet) and the circadian expression of clock and metabolic genes was measured. RESULTS: Serum of the 3Mdiet group led to increased amplitudes and daily mRNA levels of the positive limb of the circadian clock (Clock, Bmal1, Rorα). In parallel, serum of the 3Mdiet group led to the downregulation of the negative limb of the circadian clock (Cry1 and Per1), compared to both baseline and 6Mdiet. In contrast, serum of the 6Mdiet group led to a more distorted expression pattern. The catabolic genes Sirt1 and Ampk were significantly upregulated only by serum of the 3Mdiet group. CONCLUSIONS: Our results show that serum of type 2 diabetes patients consuming the 3Mdiet contains soluble factors that reset circadian rhythms leading to an expression pattern similar to that of healthy people. This clock pattern contributes to improved glucose metabolism.

REV-ERBα alters circadian rhythms by modulating mTOR signaling.

REV-ERBα is a nuclear receptor that inhibits Bmal1 transcription as part of the circadian clock molecular mechanism. Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell and whole-body energy homeostasis, that serves as an important link between metabolism and circadian clock, in part, by regulating BMAL1 activity. While the connection of REV-ERBα to the circadian clock molecular mechanism is well characterized, the interaction between mTORC1, REV-ERBα and the circadian clock machinery is not very clear. We used leucine and rapamycin to modulate mTORC1 activation and evaluate this effect on circadian rhythms. In the liver, mTORC1 was inhibited by leucine. REV-ERBα overexpression activated the mTORC1 signaling pathway via transcription inhibition of mTORC1 inhibitor, Tsc1, antagonizing the effect of leucine, while its silencing downregulated mTORC1 signaling. Activation of mTORC1 led to increased BMAL1 phosphorylation. Activation as well as inhibition of mTORC1 led to altered circadian rhythms in mouse muscle. Inhibition of liver mTORC1 by leucine or rapamycin led to low-amplitude circadian rhythms. In summary, our study shows that leucine inhibits liver mTORC1 pathway leading to dampened circadian rhythms. REV-ERBα activates the mTORC1 pathway, leading to phosphorylation of the clock protein BMAL1.

Development of Criteria for a Positive Front-of-Package Food Labeling: The Israeli Case.

Efforts to shape the food environment are aimed at reducing diet-related co-morbidities. Front-of-package labeling (FOPL) may support the consumers to make an informed decision at the point of purchase and encourage industry to reformulate food products. The Israeli Ministry of Health (MOH) implemented a unique FOPL system, using two colors: A mandatory warning (red) label alongside a voluntary positive (green) label. An independent Scientific Committee, from academia, the healthcare system, and MOH was appointed to determine the core principles for the positive FOPL. The criteria were based on the Mediterranean diet principles, with adjustments to the Israeli dietary habits, focusing on the health advantages of the food and considering its processing level. The food products eligible for positive FOPL are foods in their natural form or with added spices or herbs, or those that underwent minimal processing, with no food additives. Based on population consumption data, 19.8% of food products were eligible for positive FOPL; of them, 54% were fruits and vegetables, 20% dairy, and 14% grains. An evaluation plan is needed to assess the degree of acceptance of the positive FOPL by the industry, retailers, and the public, and its impact on food consumption and on public health.

REV-ERBα activates the mTOR signalling pathway and promotes myotubes differentiation.

BACKGROUND INFORMATION: Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell and whole-body energy homoeostasis. REV-ERBα is a nuclear receptor that plays an important role in metabolism. While mTORC1 activation is necessary for muscle differentiation, the role of REV-ERBα is less clear. RESULTS: We studied the effect of REV-ERBα overexpression and silencing as well as mTORC1 activation and inhibition on the differentiation of C2C12 myoblasts to myotubes. mTOR, myogenin and REV-ERBα were induced during differentiation of myoblasts into myotubes. REV-ERBα was found to activate mTORC1 during the differentiation process even in the absence of the differentiation medium. This activation was presumably through the downregulation of the expression of TSC1, an mTORC1 inhibitor. CONCLUSION: Herein we show that REV-ERBα promotes myoblasts differentiation via the activation of the mTORC1 signalling pathway. SIGNIFICANCE: REV-ERBα modulation can activate mTORC1 signalling and promote myoblasts differentiation.

Clock Gene Disruption Is an Initial Manifestation of Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Sleep disruption modifies the immune system and can trigger flares of inflammatory bowel diseases (IBD). Changes in expression of clock genes have been reported in patients with IBD. We investigated whether a change in the circadian clock is an early event in development of IBD. METHODS: We performed a prospective study of patients younger than 21 years old who underwent diagnostic endoscopies at the pediatric and adult gastroenterology units at the Tel Aviv Sourasky Medical Center from August 2016 through August 2017. Questionnaires were completed by 32 patients with IBD (8-21 years old) and 18 healthy individuals (controls) that provided data on demographics, sleep, disease activity scores. We also obtained data on endoscopic scores, anthropometric parameters, blood level of C-reactive protein (CRP), and fecal level of calprotectin. Peripheral blood and intestinal mucosa samples were analyzed for expression levels of clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1, and PER2). RESULTS: Levels of CRP and fecal calprotectin were significantly higher in patients with IBD compared with controls (P<.05). Expression levels of clock genes (CLOCK, CRY1, CRY2, PER1, and PER2) were significantly lower in inflamed intestinal mucosa from patients compared with intestinal mucosa from controls (P<.05). Expression levels of all clock genes except for PER2, were also significantly lower in non-inflamed intestinal mucosal tissues from patients compared with controls (P<.05). Expression levels of clock genes (CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2) were lower in white blood cells from patients with IBD compared with controls. This reduction was greater in white blood cells from patients with ulcerative colitis than in patients with Crohn's disease. CONCLUSION: Young, newly diagnosed, untreated patients with IBD have reduced expression of clock genes in inflamed and non-inflamed intestinal mucosal samples, and also in blood cells, compared with healthy individuals. Alterations in expression of clock genes might be an early event in IBD pathogenesis. ClinicalTrials.gov Identifier: NCT03662646.

Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes.

Saturated fatty acids, such as palmitate, lead to circadian disruption. We aimed at studying the effect of low doses of palmitate on circadian metabolism and to decipher the mechanism by which fatty acids convey their effect in adipocytes. Mice were fed non-obesogenic doses of palm or olive oil and adipocytes were treated with palmitate and oleate. Cultured adipocytes treated with oleate showed increased AMPK activity and induced the expression of mitochondrial genes indicating increased fatty acid oxidation, while palmitate increased ACC activity and induced the expression of lipogenic genes, indicating increased fatty acid synthesis. Low doses of palmitate were sufficient to alter circadian rhythms, due to changes in the expression and/or activity of key metabolic proteins including GSK3ß and AKT. Palmitate-induced AKT and GSK3ß activation led to the phosphorylation of BMAL1 that resulted in low levels as well as high amplitude of circadian clock expression. In adipocytes, the detrimental metabolic alteration of palmitate manifests itself early on even at non-obesogenic levels. This is accompanied by modulating BMAL1 expression and phosphorylation levels, which lead to dampened clock gene expression.

Serotonin Prevents Differentiation of Brown Adipocytes by Interfering with Their Clock.

OBJECTIVE: Serotonin was shown to interfere with the differentiation of brown adipocytes. In addition, clock components inhibit brown adipogenesis through direct transcriptional control of key components of the transforming growth factor ß pathway. The aim of this study was to investigate whether serotonin abrogates brown adipogenesis by affecting clock functionality. METHODS: Nondifferentiated and differentiated HIB1B brown adipocytes were treated with serotonin, and their clock expression and functionality and differentiation state were examined. RESULTS: Nondifferentiated HIB1B brown adipocytes treated with serotonin showed increased brown adipocyte markers alongside increased brain-muscle Arnt-like protein 1 (Bmal1) and RAR related orphan receptor A (Rora) but decreased nuclear receptor Rev-erbα mRNA levels. BMAL1 overexpression together with serotonin led to significantly lower brown adipocyte markers. Serotonin in the differentiation cocktail led to reduced brown adipocyte markers as well as clock gene expression. After differentiation, serotonin treatment significantly decreased brown adipocyte markers and reduced BMAL1 and RORα but increased REV-ERBα protein levels. Addition of serotonin to the differentiation medium or addition after differentiation reduced activity of calcium/calmodulin-dependent protein kinase type II subunit gamma, which interferes with circadian locomoter output cycles protein kaput (CLOCK):BMAL1 dimerization and transactivation. CONCLUSIONS: Clock expression is required at the early stages of differentiation to brown adipocytes, and serotonin interferes with this process by modulating clock functionality. Serotonin interferes with clock functionality by reducing the levels of the active form of calcium/calmodulin-dependent protein kinase type II subunit gamma.

Reduction in Glycated Hemoglobin and Daily Insulin Dose Alongside Circadian Clock Upregulation in Patients With Type 2 Diabetes Consuming a Three-Meal Diet: A Randomized Clinical Trial.

OBJECTIVE: In type 2 diabetes, insulin resistance and progressive ß-cell failure require treatment with high insulin doses, leading to weight gain. Our aim was to study whether a three-meal diet (3Mdiet) with a carbohydrate-rich breakfast may upregulate clock gene expression and, as a result, allow dose reduction of insulin, leading to weight loss and better glycemic control compared with an isocaloric six-meal diet (6Mdiet). RESEARCH DESIGN AND METHODS: Twenty-eight volunteers with diabetes (BMI 32.4 ± 5.2 kg/m2 and HbA1c 8.1 ± 1.1% [64.5 ± 11.9 mmol/mol]) were randomly assigned to 3Mdiet or 6Mdiet. Body weight, glycemic control, continuous glucose monitoring (CGM), appetite, and clock gene expression were assessed at baseline, after 2 weeks, and after 12 weeks. RESULTS: 3Mdiet, but not 6Mdiet, led to a significant weight loss (-5.4 ± 0.9 kg) (P < 0.01) and decreased HbA1c (-12 mmol/mol [-1.2%]) (P < 0.0001) after 12 weeks. Fasting glucose and daily and nocturnal glucose levels were significantly lower on the 3Mdiet. CGM showed a significant decrease in the time spent in hyperglycemia only on the 3Mdiet. Total daily insulin dose was significantly reduced by 26 ± 7 units only on the 3Mdiet. There was a significant decrease in the hunger and cravings only in the 3Mdiet group. Clock genes exhibited oscillation, increased expression, and higher amplitude on the 3Mdiet compared with the 6Mdiet. CONCLUSIONS: A 3Mdiet, in contrast to an isocaloric 6Mdiet, leads to weight loss and significant reduction in HbA1c, appetite, and overall glycemia, with a decrease in daily insulin. Upregulation of clock genes seen in this diet intervention could contribute to the improved glucose metabolism.

Non-obesogenic doses of fatty acids modulate the functionality of the circadian clock in the liver.

Saturated fatty acids, such as palmitate, lead to circadian disruption in cell culture. Moreover, information regarding the effects of unsaturated fatty acids on circadian parameters is scarce. We aimed at studying the effects of low doses of saturated as well as unsaturated fatty acids on circadian metabolism in vivo and at deciphering the mechanism by which fatty acids convey their effect. Mice were fed non-obesogenic doses of palm or olive oil and hepatocytes were treated with palmitate and oleate. Mice fed non-obesogenic doses of palm oil showed increased signaling towards fatty acid synthesis, while olive oil increased signaling towards fatty acid oxidation. Low doses of palmitate and oleate were sufficient to alter circadian rhythms, due to changes in the expression and/or activity of key metabolic proteins. Palmitate, but not oleate, counteracted the reduction in lipid accumulation and BMAL1-induced expression of mitochondrial genes involved in fatty acid oxidation. Palmitate was also found to interfere with the transcriptional activity of CLOCK:BMAL1 by preventing BMAL1 deacetylation and activation. In addition, palmitate, but not oleate, reduced PER2-mediated transcriptional activation and increased REV-ERBα-mediated transcriptional inhibition of Bmal1. The inhibition of PER2-mediated transcriptional activation by palmitate was achieved by interfering with PER2 nuclear translocation. Indeed, PER2 reduced fat accumulation in hepatocytes and this reduction was prevented by palmitate. Herein, we show that the detrimental metabolic alteration seen with high doses of palmitate manifests itself early on even with non-obesogenic levels. This is achieved by modulating BMAL1 at several levels abrogating its activity and expression.

The Circadian Clock Drives Mast Cell Functions in Allergic Reactions.

Allergic diseases are known to vary in the severity of their symptoms throughout the day/night cycle. This rhythmicity is also observed in mast cell function and responsiveness. Mast cells are key effector cells of allergic reactions and release cytokines, chemokines, and important inflammatory mediators such as histamine, which have been shown to display diurnal variation. Recent research clarified that mast cells are controlled by their internal clock-which is regulated by a specific set of clock genes-as well as external factors such as light sensed by the suprachiasmatic nuclei, hormonal status, or diet. Here, we give an overview of the connections between circadian clock, mast cells, and allergic disease. Further work aimed at studying the role of chronotherapy/chronomedicine should take into account this rhythmic nature of not only mast cells but also the immune responses generated by mast cell signaling.