Circadian pacemakers orchestrate behavioral and physiological rhythms, enabling organisms to anticipate daily reoccurring environmental events such as light and dark, temperature changes, and food availability. When nocturnal rodents are subjected to time-restricted feeding during the day, they typically display food anticipatory activity several hours before mealtime. Upon releasing mice to ad libitum feeding, this anticipatory activity is abolished immediately but, following food deprivation, reappears at approximately the same time. However, the mechanism by which rodents retain this time memory of food availability during ad libitum feeding has remained elusive. We utilized the open-source Feeding Experimentation Device 3 (FED3) to measure food-seeking nose-poking behavior. We programmed the FED3 to dispense a pellet by a single left nose-poke, but not by right poke. During daytime restricted feeding, mice exhibited strong anticipatory nose-poking a few hours prior to the daytime meal in both rewarded left and unrewarded right pokes. In addition, mice also exhibited elevation of both rewarded and unrewarded pokes at night, coinciding with mice's previous habitual feeding time. Following ad libitum feeding, rewarded daytime nose-poking gradually moved back to habitual nighttime. However, following food deprivation, anticipatory poking immediately reappeared during the day and night, coinciding with the times of previous daytime restricted feeding and nighttime habitual feeding. Under ad libitum feeding, db/db mice didn't exhibit a clear daily rhythm in food intake. However, these mice exhibited robust food anticipation in both nose-pokes and activity during daytime restricted feeding. Following release back to ad libitum feeding, db/db mice poked sporadically during the day and night, and following food deprivation, anticipation promptly reappeared. These data suggest that there are at least two oscillators underlying food anticipation: one oscillator with a phase that changes according to food availability, and another oscillator with a phase unaffected by feeding conditions. In db/db mice, the first oscillator is likely impaired, and the second oscillator is unaffected.

Circadian disruption is pervasive in modern society and associated with increased risk of disease. Chronic jet lag paradigms are popular experimental tools aiming to emulate human circadian disruption experienced during rotating and night shift work. Chronic jet lag induces metabolic phenotypes tied to liver and systemic functions, yet lack of a clear definition for how rhythmic physiology is impaired under these conditions hinders the ability to identify the underlying molecular mechanisms. Here, we compared 2 common chronic jet lag paradigms and found that neither induced arrythmicity of the liver and each had distinct effects on rhythmicity. Instead, more frequent 8-h forward shifts of the light schedule induced more severe misalignment and non-fasted hyperglycemia. Every other day shifts eventually uncoupled behavioral and hepatic rhythms from the light cycle, reminiscent of free-running conditions. These results point to misalignment, not arrhythmicity, as the initial disturbance tied to metabolic dysfunction in environmental circadian disruption and highlight considerations for the interpretation and design of chronic jet lag studies.

Disruptions of circadian rhythms are widespread in modern society and lead to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle-specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high-fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from Bmal1-deficient muscles revealed impaired glucose utilization specifically at early steps in glycolysis that dictate the switch between anabolic and catabolic glucose fate. We provide evidence that this is due to abnormal control of the nutrient stress-responsive hypoxia-inducible factor (HIF) pathway. Genetic HIF1α stabilization in muscle Bmal1-deficient mice restores glucose tolerance and expression of 217/736 dysregulated genes during DIO, including glycolytic enzymes. Together, these data indicate that during DIO, skeletal muscle BMAL1 is an important regulator of HIF-driven glycolysis and metabolic flexibility, which influences the development of high-fat-diet-induced glucose intolerance.

The impact of dietary patterns on health and lifespan is well-established, yet the effects of meal timing on the aging process and risk of premature death remain unclear. This study aimed to investigate the association between the difference in energy and macronutrient intake at dinner versus breakfast and the risk of premature mortality and biological aging.

Utilizing data from the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2014, a cohort of 27,261 adults was examined. Dietary data were collected through 24-h dietary recalls, and Cox proportional hazards models and binary logistic regression models were used to assess the risk of premature death and indicators of biological aging.

Individuals with higher energy and protein intake at dinner compared to breakfast exhibited an increased risk of premature death and higher biological aging indicators. Isocaloric substitution of energy and macronutrients from breakfast to dinner significantly increased the risk of aging.

The difference in energy and macronutrient intake at dinner versus breakfast is closely associated with the risk of premature death and biological aging. The findings underscore the potential impact of meal timing on metabolic health and lifespan extension.

Calorie-rich foods, particularly those that are high in fat and sugar, evoke pleasure in both humans and animals1. However, prolonged consumption of such foods may reduce their hedonic value, potentially contributing to obesity2-4. Here we investigated this phenomenon in mice on a chronic high-fat diet (HFD). Although these mice preferred high-fat food over regular chow in their home cages, they showed reduced interest in calorie-rich foods in a no-effort setting. This paradoxical decrease in hedonic feeding has been reported previously3-7, but its neurobiological basis remains unclear. We found that in mice on regular diet, neurons in the lateral nucleus accumbens (NAcLat) projecting to the ventral tegmental area (VTA) encoded hedonic feeding behaviours. In HFD mice, this behaviour was reduced and uncoupled from neural activity. Optogenetic stimulation of the NAcLat→VTA pathway increased hedonic feeding in mice on regular diet but not in HFD mice, though this behaviour was restored when HFD mice returned to a regular diet. HFD mice exhibited reduced neurotensin expression and release in the NAcLat→VTA pathway. Furthermore, neurotensin knockout in the NAcLat and neurotensin receptor blockade in the VTA each abolished optogenetically induced hedonic feeding behaviour. Enhancing neurotensin signalling via overexpression normalized aspects of diet-induced obesity, including weight gain and hedonic feeding. Together, our findings identify a neural circuit mechanism that links the devaluation of hedonic foods with obesity.

Physiological processes, including metabolism and immune responses, are generated by the circadian clock, driven by clock genes. Disrupting circadian rhythms through a high-fat diet promotes obesity and inflammation. Studies show that deleting the clock gene, brain, and muscle ARNT-like 1 (Bmal1) in adipose tissue leads to overeating and weight gain. We now show that Bmal1 deletion in neutrophils protects against diet-induced obesity and reduces inflammatory macrophage infiltration into epididymal white adipose tissue (eWAT), despite increased food intake over 20 weeks of a high-fat diet. This protection is linked to enhanced energy expenditure, increased UCP1 expression in iBAT, improved insulin sensitivity, and altered expression of genes encoding chemokine receptors CXCR2, CXCR4, and the ligand Cxcl2 in eWAT. Our findings reveal a key role of Bmal1 in neutrophils in regulating high-fat diet-induced adipose inflammation and emphasize circadian regulation's importance in immuno-metabolic function.

When food is freely available, eating occurs without energy deficit. While agouti-related peptide (AgRP) neurons are likely involved, their activation is thought to require negative energy balance. To investigate this, we implemented long-term, continuous in vivo fiber-photometry recordings in mice. We discovered new forms of AgRP neuron regulation, including fast pre-ingestive decreases in activity and unexpectedly rapid activation by fasting. Furthermore, AgRP neuron activity has a circadian rhythm that peaks concurrent with the daily feeding onset. Importantly, this rhythm persists when nutrition is provided via constant-rate gastric infusions. Hence, it is not secondary to a circadian feeding rhythm. The AgRP neuron rhythm is driven by the circadian clock, the suprachiasmatic nucleus (SCN), as SCN ablation abolishes the circadian rhythm in AgRP neuron activity and feeding. The SCN activates AgRP neurons via excitatory afferents from thyrotrophin-releasing hormone-expressing neurons in the dorsomedial hypothalamus (DMHTrh neurons) to drive daily feeding rhythms.

All skin layers and cutaneous appendages harbor a robust circadian clock, whose phase is under the influence of light through the central clock in the suprachiasmatic nucleus. The skin clock coordinates fundamental biological processes, including metabolism and stem cell activation. It also prominently modulates activity of skin-resident immune cells and the inflammatory response. Numerous diurnally regulated genes in the skin have been implicated in skin diseases in GWASs. Therefore, the mouse skin is a powerful model for understanding the diverse roles of circadian biology in maintaining tissue health and the initiation and propagation of disease states. When planning experiments to study the circadian biology of mouse skin, multiple technical and biological factors must be carefully considered. In this paper, we provide comprehensive guidance on the general circadian experimental design and associated housing for the mice. We highlight the importance of aligning sample collection with the desired hair cycle stage and animal age. We introduce methods to disrupt the clock in the skin, including altering light and feeding schedules as well as using transgenic mouse models. Finally, we discuss the use of transcriptomic data, both bulk and single cell, for circadian studies.

The constant expansion of the field of metabolic research has led to more nuanced and sophisticated understanding of the complex mechanisms that underlie metabolic functions and diseases. Collaborations with scientists of various fields such as neuroscience, immunology and drug discovery have further enhanced the ability to probe the role of metabolism in physiological processes. However, many behaviours, endocrine and biochemical processes, and the expression of genes, proteins and metabolites have daily ~24-h biological rhythms and thus peak only at specific times of the day. This daily variation can lead to incorrect interpretations, lack of reproducibility across laboratories and challenges in translating preclinical studies to humans. In this Review, we discuss the biological, environmental and experimental factors affecting circadian rhythms in rodents, which can in turn alter their metabolic pathways and the outcomes of experiments. We recommend that these variables be duly considered and suggest best practices for designing, analysing and reporting metabolic experiments in a circadian context.

Thermogenesis of brown adipose tissue (BAT) provides metabolic benefits against pathologic conditions, such as type 2 diabetes, obesity, cardiovascular disease, and cancer. The thermogenic function of BAT relies on mitochondria, but whether mitochondrial remodeling is required for the beneficial effects of BAT remains unclear. We recently identified FAM210A as a BAT-enriched mitochondrial protein essential for cold-induced thermogenesis through the modulation of OPA1-dependent cristae remodeling. Here, we report a key role of FAM210A in the systemic response to a high-fat diet (HFD). We discovered that an HFD suppressed FAM210A expression, associated with excessive OPA1 cleavage in BAT. Ucp1-Cre-driven BAT-specific Fam210a knockout (Fam210aUKO) similarly elevated OPA1 cleavage, accompanied by whitening of BAT. When subjected to an HFD, Fam210aUKO mice gained similar fat mass as sibling control mice but developed glucose intolerance, insulin resistance, and liver steatosis. The metabolic dysfunction was associated with overall increased lipid content in both the liver and BAT. Additionally, Fam210aUKO leads to inflammation in white adipose tissue. These data demonstrate that FAM210A in BAT is necessary for counteracting HFD-induced metabolic dysfunction but not obesity.

FAM210A regulates cold-induced mitochondrial remodeling through control of OPA1 cleavage, but whether it also plays a role in high-fat diet (HFD)-induced cristae remodeling is unknown. We asked if an HFD would alter the FAM210A level and OPA1 cleavage in brown adipose tissue (BAT) and how FAM210A loss of function would affect diet-induced obesity in mice. We found that an HFD diminished FAM210A expression and accelerated OPA1 cleavage in BAT, and Fam210a knockout exacerbated HFD-induced whitening of BAT, cold intolerance, liver steatosis, white adipose tissue inflammation, and metabolic dysfunction. Our work reveals a physiologic role of FAM210A-mediated BAT mitochondrial remodeling in systemic adaptation to an HFD and suggests that BAT mitochondria may be targeted to treat diet-induced metabolic dysfunction.

Circadian rhythms in humans are biological rhythms that regulate various physiological processes within a 24-hour time frame. Critical illness can disrupt the circadian rhythm, as can environmental and clinical factors, including altered light exposure, organ replacement therapies, disrupted sleep-wake cycles, noise, continuous enteral feeding, immobility, and therapeutic interventions. Nonpharmacological interventions, controlling the ICU environment, and pharmacological treatments are among the treatment strategies for circadian disruption. Nutrition establishes biological rhythms in metabolically active peripheral tissues and organs through appropriate synchronization with endocrine signals. Therefore, adhering to a feeding schedule based on the biological clock, a concept known as "chrononutrition," appears to be vitally important for regulating peripheral clocks. Chrononutritional approaches, such as intermittent enteral feeding that includes overnight fasting and consideration of macronutrient composition in enteral solutions, could potentially restore circadian health by resetting peripheral clocks. However, due to the lack of evidence, further studies on the effect of chrononutrition on clinical outcomes in critical illness are needed. The purpose of this review was to discuss the role of chrononutrition in regulating biological rhythms in critical illness, and its impact on clinical outcomes.

Obstructive sleep apnea (OSA) is a global public health issue. Life's Crucial 9 (LC9) is recognized as a powerful tool for assessing cardiovascular health. Although the etiology of OSA remains unclear, saturated fatty acids (SFAs) and cardiovascular health are increasingly regarded as a non-negligible element. This study aims to assess the association between dietary intake of SFAs and the risk of OSA, and the mediating effect of LC9.

Based on the National Health and Nutrition Examination Survey (NHANES), dietary questionnaires of participant were collected, and the average values of 24-h dietary recall data over 2 days were obtained. A continuous cross-sectional analysis with dietary energy adjustment was employed. Weighted multivariable logistic regression models were used to estimate the weighted odds ratios (ORs) and their 95% confidence intervals (CIs) for SFAs and OSA. Evaluate the mediating role of LC9 in the relationship between SFAs and OSA.

A total of 13,563 participants aged 20 years and above were included in this study. The intakes of Sfa 4.0 and LC9 among participants with OSA were significantly lower than those in the normal population. After adjusting for confounding factors, total SFAs could increase the risk of OSA [Model 1, Q3, 0.03, 1.49 (1.03, 2.15); Model 2, Q3, 0.04, 1.47 (1.01, 2.13)]. It was emphasized that dietary intake of Sfa 12.0, Sfa 14.0, and Sfa 16.0 were protective factors for OSA, especially among participants aged 45-64 years and white individuals. Moreover, Sfa 12.0 exhibited a better protective effect in female participants [Q3, 0.04, 0.66 (0.45, 0.99)]. In addition, the cardiovascular health score - LC9 had a mediating effect in Sfa4.0 on OSA [Proportion of mediation: -0.035, 95% CI: (-0.058, -0.01); p= 0.002]. There was a nonlinear relationship between dietary intake of Sfa 12.0, Sfa 16.0, and Sfa 18.0 and OSA (P-Nonlinear = 0.013).

These findings suggest that dietary mixtures of saturated fatty acids increase the risk of OSA. Among them, SFA 4:0 can increase the risk of OSA through the level of cardiovascular health. However, contrary to traditional beliefs, long-chain saturated fatty acids can reduce the risk of OSA.

This review summarizes recent evidence for a role of the clock in adipose tissue physiology and the impact of circadian desynchrony on the development of obesity.

Circadian disruptions due to shift work, late time eating and nighttime light exposure are associated with obesity and its metabolic and cardiovascular consequences. Studies in mice harboring tissue-specific gain/loss of function mutations in clock genes revealed that the circadian clock acts on multiple pathways to control adipogenesis, lipogenesis/lipolysis and thermogenesis. Time-restricted eating (TRE), aligning feeding with the active period to restore clock function, represents a promising strategy to curb obesity. While TRE has shown clear benefits, especially in participants at higher cardiometabolic risk, current studies are limited in size and duration. Larger, well-controlled studies are warranted to conclusively assess the effects of TRE in relation to the metabolic status and gender. Field studies in shift-workers, comparing permanent night shift versus rotating shifts, are also necessary to identify the optimal time window for TRE.

Tissue-level oscillation is achieved by tissue-intrinsic clocks along with network-dependent signals originating from distal organs and organismal behavior. Yet, it remains unexplored whether maternal circadian rhythms during pregnancy influence fetal rhythms and impact long-term susceptibility to dietary challenges in offspring. Here, we demonstrate that circadian disruption during pregnancy decreased placental and neonatal weight yet retained transcriptional and structural maturation. Intriguingly, diet-induced obesity was exacerbated in parallel with arrhythmic feeding behavior, hypothalamic leptin resistance, and hepatic circadian reprogramming in offspring of chronodisrupted mothers. In utero circadian desynchrony altered the phase-relationship between the mother and fetus and impacted placental efficiency. Temporal feeding restriction in offspring failed to fully prevent obesity, whereas the circadian alignment of caloric restriction with the onset of the active phase virtually ameliorated the phenotype. Thus, maternal circadian rhythms during pregnancy confer adaptive properties to metabolic functions in offspring and provide insights into the developmental origins of health and disease.

Obesity and circadian rhythm disruption are significant global health concerns, contributing to an increased risk of metabolic disorders. Both adipose tissue and circadian rhythms play critical roles in maintaining energy homeostasis, and their dysfunction is closely linked to obesity. This study aimed to assess the effects of chronic low-dose SR9009, a REV-ERB ligand, on circadian disruption induced by constant light exposure in mice.

Mice were exposed to constant light for eight weeks (LL mice), resulting in increased body weight, insulin resistance, white fat mass, and altered circadian clock gene expression. Low-dose SR9009 (10 mg/kg daily) was administered chronically to assess its impact on these metabolic disruptions.

LL mice treated with SR9009 for eight weeks showed reduced weight gain, insulin resistance, and white fat mass but no significant impact on overall energy homeostasis. SR9009 suppressed Bmal1 expression and restored Rev-erbα and Rev-erbβ expression in white and brown adipose tissue (WAT and BAT). In vitro studies using 3T3-L1 cells indicated that SR9009 inhibited adipogenesis, leading to further investigation in vivo. SR9009 restored ChREBP1a and Srebp-1c expression in BAT but did not affect inflammatory cytokine or adipokine gene expression, nor did it restore Fasn, Pparγ, and Prom1 expression in both WAT and BAT.

These findings suggest that SR9009 may be a potential therapeutic for preventing weight gain and insulin resistance caused by circadian disruptions, likely through adipogenesis inhibition, though its effects on other metabolic pathways remain limited at low doses.

While the effect of time-of-day (morning versus evening) on hormones, lipids and lipolysis has been studied in relation to meals and exercise, there are no studies that have investigated the effects of time-of-day on ice bath induced hormone and lipidome responses. In this crossover-designed study, a group of six women and six men, 26 ± 5 years old, 176 ± 7 cm tall, weighing 75 ± 10 kg, and a BMI of 23 ± 2 kg/m2 had an ice bath (8-12 °C for 5 min) both in the morning and evening on separate days. Absence from intense physical exercise, nutrient intake and meal order was standardized in the 24 h prior the ice baths to account for confounders such as diet or exercise. We collected venous blood samples before and after (5 min and 30 min) the ice baths to measure hormones (noradrenaline, adrenaline, and cortisol) and lipid levels in plasma via liquid chromatography mass spectrometry shotgun lipidomics. We found that ice baths in the morning increase plasma fatty acids more than in the evening. Overall plasma lipid composition significantly differed in-between the morning and evening, and only in the morning ice bathing is accompanied by significantly increased plasma fatty acids from 5.1 ± 2.2% to 6.0 ± 2.4% (P = 0.029) 5 min after and to 6.3 ± 3.1% (P = 0.008) 30 min after. Noradrenaline was not affected by time-of-day and increased significantly immediately after the ice baths in the morning by 127 ± 2% (pre: 395 ± 158 pg/ml, post 5 min: 896 ± 562 pg/ml, P = 0.025) and in the evening by 144 ± 2% (pre: 385 ± 146 pg/ml, post 5 min: 937 ± 547 pg/ml, P = 0.015). Cortisol was generally higher in the morning than in the evening (pre: 179 ± 108 pg/ml versus 91 ± 59 pg/ml, P = 0.013; post 5 min: 222 ± 96 pg/ml versus 101 ± 52 pg/ml, P = 0.001; post 30 min: 190 ± 96 pg/ml versus 98 ± 54 pg/ml, P = 0.009). There was no difference in the hormonal and lipidome response to an ice bath between women and men. The main finding of the study was that noradrenaline, adrenaline, cortisol and plasma lipidome responses are similar after an ice bath in the morning and evening. However, ice baths in the morning increase plasma fatty acids more than in the evening.

Disrupted feeding and fasting cycles as well as chronic high-fat diet-induced (HFD-induced) obesity are associated with cardiovascular disease risk factors. We designed studies that determined whether 2 weeks of time-restricted feeding (TRF) intervention in mice fed a chronic HFD would reduce cardiovascular disease risk factors. Mice were fed a normal diet (ND; 10% fat) ad libitum or HFD (45% fat) for 18 weeks ad libitum to establish diet-induced obesity. ND or HFD mice were continued on ad libitum diet or subjected to TRF (limiting food availability to 12 hours only during the dark phase) during the final 2 weeks of the feeding protocol. TRF improved whole-body metabolic diurnal rhythms without a change in body weight. HFD mice showed reduced blood pressure dipping compared with ND, which was restored by TRF. Further, TRF reduced aortic wall thickness, decreased aortic stiffness, as well as increased kidney tubular brush border integrity, decreased renal medullary fibrosis, and reduced renal medullary T cell inflammation in HFD mice. These findings indicate that TRF may be an effective intervention for improving vascular and kidney health in a model of established diet-induced obesity.

Anxiety is a common co-morbidity with obesity and metabolic disease, and can lead to a significant impact on quality of life. The vast differences in the gut microbiota between obese and control individuals provide a potential avenue for therapeutic intervention. A high-fat diet (HFD) in rodent models have been shown to induce anxiety-like behaviour and has been tested through an array of distinct behavioural tests such as the elevated plus maze test, light-dark test and open field test. Despite differences in testing and assessment parameters, the behavioural outcomes have previously yielded similar results. Recent evidence suggests that HFD has an anxiolytic effect on mice, complicating the model. Here, we aimed to confirm whether HFD-fed mice are more susceptible to presenting anxiety-like behaviours. Our findings showed no significant differences in behaviour, plasma corticosterone and inflammation markers between HFD and control diet (CTD) mice, despite considerable differences in adiposity and faecal microbial communities. Additionally, daily oral gavage is one of the most common methods for testing bacterial probiotics in rodent models, but this handling could potentially also cause stress to the mice. Thus, we investigated if daily oral gavage could mask differences in HFD and CTD mice. We found no significant differences in weight, fat mass or anxiety-like behaviour in CTD-fed mice with or without daily oral gavage.

Current lifestyles include calorie-dense diets and late-night food intake, which can lead to circadian misalignment. Our group recently demonstrated that sweet treats before bedtime alter the clock system in healthy rats, increasing metabolic risk factors. Therefore, we aimed to assess the impact of the sweet treat consumption time on the clock system in rats fed a cafeteria diet (CAF). Moreover, since flavanols have demonstrated beneficial effects in metabolic disorders and clock gene modulation, we also investigated whether these phenolic compounds can restore the circadian disruption caused by these altered dietary patterns. For this, 64 Fisher rats were fed CAF for 9 weeks. In the last 4 weeks, animals were daily administered a low dose of sugar (160 mg/kg) as a sweet treat at 8 a.m. (ZT0) or 8 p.m. (ZT12). Two other groups received 25 mg/kg of grape seed flavanols in addition to sweet treats. Finally, the animals were sacrificed at different time points (9 a.m., 3 p.m., 9 p.m., and 3 a.m.). The results showed that metabolic and circadian disturbances by CAF may be influenced by the time of sugar administration, slightly reinforcing the alterations in diurnal rhythmicity of serum biochemical parameters, hormones, and hypothalamic genes with bedtime snacking. Flavanols improved metabolic health and restored the oscillation of biochemical parameters, hormones, and clock and appetite-signaling genes, showing greater effects at ZT12. These results highlight the importance of meal timing in influencing physiological and metabolic outcomes, even under calorie-dense diets. Moreover, they also suggest the zeitgeber role of flavanols, modulating the clock system and contributing to an improved metabolic profile under different feeding pattern conditions.

Eating behaviour and circadian rhythms are closely related. The type, timing, and quantity of food consumed, and host circadian rhythms, directly influence the intestinal microbiota, which in turn impacts host circadian rhythms and regulates food intake beyond homeostatic eating. This Opinion discusses the impact of food intake and circadian disruptions induced by an obesogenic environment on gut-brain axis signalling. We also explore potential mechanisms underlying the effects of altered gut microbiota on food intake behaviour and circadian rhythmicity. Understanding the crosstalk between gut microbiota, circadian rhythms, and unhealthy eating behaviour is crucial to addressing the obesity epidemic, which remains one of the biggest societal challenges of our time.

The biological reproductive process requires the precise coordination of annual and daily signals to adapt to environmental shifts. Humans and animals have developed shared neuroendocrine systems that have adapted to process daily and seasonal light signals within the hypothalamic-pituitary -gonadal axis. However, the stability of circadian and seasonal biological processes is at risk due to industrialization and contemporary round-the-clock lifestyles. These threats include skipping breakfast, excessive artificial illumination during inappropriate hours because of irregular work schedules, nighttime urban lighting, and widespread environmental pollution from endocrine-disrupting chemicals. This review aimed to explore the interplay between lifestyle factors, circadian rhythms, and reproductive functions.

This review examined the reciprocal influences of circadian clocks on reproductive hormones, exploring the underlying mechanisms and their implications for fertility and reproductive health. We emphasized key findings regarding molecular clock components, endocrine pathways, and the critical importance of synchronizing circadian rhythms with hormonal cycles.

The intersection of reproductive endocrinology and circadian biology reveals complex interactions between hormonal regulation and circadian rhythms. Circadian rhythm misalignments due to environmental factors, including late-night work and skipping breakfast, negatively impact endocrine and reproductive functions.

More strategies are needed to mitigate the effects of circadian disruption on reproductive functions.

Intermittent fasting remains a safe and effective strategy to ameliorate various age-related diseases, but its specific mechanisms are not fully understood. Considering that transcription factors (TFs) determine the response to environmental signals, here, we profiled the diurnal expression of 600 samples across four metabolic tissues sampled every 4 over 24 h from mice placed on five different feeding regimens to provide an atlas of TFs in biological space, time, and feeding regimen. Results showed that 1218 TFs exhibited tissue-specific and temporal expression profiles in ad libitum mice, of which 974 displayed significant oscillations at least in one tissue. Intermittent fasting triggered more than 90% (1161 in 1234) of TFs to oscillate somewhere in the body and repartitioned their tissue-specific expression. A single round of fasting generally promoted TF expression, especially in skeletal muscle and adipose tissues, while intermittent fasting mainly suppressed TF expression. Intermittent fasting down-regulated aging pathway and upregulated the pathway responsible for the inhibition of mammalian target of rapamycin (mTOR). Intermittent fasting shifts the diurnal transcriptome atlas of TFs, and mTOR inhibition may orchestrate intermittent fasting-induced health improvements. This atlas offers a reference and resource to understand how TFs and intermittent fasting may contribute to diurnal rhythm oscillation and bring about specific health benefits.

A diet containing foods that are sources of S-methylmethionine (SMM), and its use as a dietary supplement, have demonstrated beneficial health effects. Thus, the objective of this work was to evaluate the inclusion of SMM as a dietary supplement in C57BL/6J high-fat-fed mice to verify whether this compound alone would be responsible for these positive effects. Mice were divided into three groups: LF (low-fat diet), HF (high-fat diet), and HF+SMM (high-fat diet plus SMM), and maintained for 10 weeks with water and food provided ad libitum. Body weight and food intake were measured weekly, and food efficiency was calculated. In addition, at week 9, fasting glucose was measured and, after necropsy, at week 10, liver, inguinal adipose, and kidney weights were measured; triglycerides, histology, liver gene expression, serum insulin, and MCP-1 levels were also determined. Final body weight, average weight gain, and the liver/body weight of the SMM group showed a significant difference with the LF group. HF+SMM-fed mice show improved regulation in glucose metabolism, demonstrated by the assessment of fasting glucose, insulin concentration, and HOMA-IR, compared with the HF-fed group. Liver triglycerides and MCP-1 levels showed no significant differences between fed groups. By the positive gene regulation of Sult1e1, Phlda1, and Ciart, we hypothesized that SMM administration to mice may have regulated xenobiotic, glucose, and circadian rhythm pathways.

Circadian rhythms are highly conserved biorhythms of ~24 h that govern many fundamental biological processes, including cardiovascular (CV) homeostasis. Disrupting the timing of cellular oscillators promotes cellular stress, and induction of pathogenic pathways underpins the pathogenesis of many CV diseases (CVDs). Thus, shift work, late eating, sleep disturbances, and other disruptors can result in an elevated risk of heart disease and increased incidence of adverse CV events. Here, we discuss the importance of circadian rhythms for CV homeostasis, recent developments in understanding the impact of disrupted circadian rhythms on CV health and disease progression, and how understanding the interactions between circadian and CV physiology is crucial for improving interventions to mitigate CVD, especially in populations impacted by disrupted circadian rhythms.

Nearly every cell of the body contains a circadian clock mechanism that is synchronized with the light-entrained clock in the suprachiasmatic nucleus (SCN). Desynchrony between the SCN and the external environment leads to metabolic dysfunction in shift workers. Similarly, mice with markedly shortened endogenous period due to the deletion of circadian REV-ERBα/β nuclear receptors in the SCN (SCN DKO) exhibit increased sensitivity to diet-induced obesity (DIO) on a 24 h light:dark cycle while mice with REV-ERBs deleted in hepatocytes (HepDKO) display exacerbated hepatosteatosis in response to a high-fat diet. Here, we show that inducing deletion of hepatocyte REV-ERBs in SCN DKO mice (Hep-SCN DDKO) rescued the exacerbated DIO and hepatic triglyceride accumulation, without affecting the shortened behavioral period. These findings suggest that metabolic disturbances due to environmental desynchrony with the central clock are due to effects on peripheral clocks which can be mitigated by matching peripheral and central clock periods even in a desynchronous environment. Thus, maintaining synchrony within an organism, rather than between endogenous and exogenous clocks, may be a viable target for the treatment of metabolic disorders associated with circadian disruption.

This study analyzed the relation of energy and macronutrient intake at dinner versus breakfast with the risk of hyperhomocysteinemia (Hhcy).

Up to 12,474 adults, in which 1,387 with Hhcy, completed a questionnaire about energy and macronutrient intake in the National Health and Nutrition Examination. The differences (Δ) in that between dinner and breakfast (Δ = dinner - breakfast) were categorized into quartiles. Logistic regression analyses or restrictive cubic spline regressions were conducted to determine the relation in Δ and the risk of Hhcy, as well as the change in risk when 5% energy at dinner was substituted with those at breakfast through isocaloric substitution models.

After adjusted the confounders, results showed that compared to the research objects in the lowest quartile, those in the highest quartile were more prone to get Hhcy (odds ratio (OR)Δ energy = 1.26, 95% CI = 1.03-1.56; ORΔ protein = 1.25, 95% CI = 1.01-1.55; ORΔ PUFA = 1.22, 95% CI = 1.01-1.49, respectively). Isocalorically replacing 5% energy at dinner with energy at breakfast was related to 5% lower Hhcy risk. Replacing 5% of energy provided by protein at dinner with that by protein or PUFA at breakfast was related to 10% and 11% lower Hhcy risk, respectively. Replacing 5% energy provided by PUFA at dinner with that by protein or PUFA at breakfast were associated with 8% and 6% lower Hhcy risk, respectively.

The optimal intake period for energy, protein, and polyunsaturated fatty acid intake for reducing Hhcy risk in adults was the morning.

Understanding the relationship between dietary fat and physiological responses is crucial in species adapted to arid environments where water scarcity is common. In this study, we present a comprehensive exploration of gene expression across five tissues (kidney, liver, lung, gastrointestinal tract and hypothalamus) and 17 phenotypic measurements, investigating the effects of dietary fat in the desert-adapted cactus mouse (Peromyscus eremicus). We show impacts on immune function, circadian gene regulation and mitochondrial function for mice fed a lower-fat diet compared with mice fed a higher-fat diet. In arid environments with severe water scarcity, even subtle changes in organismal health and water balance can affect physical performance, potentially impacting survival and reproductive success. This study sheds light on the complex interplay between diet, physiological processes and environmental adaptation, providing valuable insights into the multifaceted impacts of dietary choices on organismal well-being and adaptation strategies in arid habitats.

Earth's rotation around its axis has pressured its inhabitants to adapt to 24 h cycles of day and night. Humans adapted their own circadian rhythms to the Earth's rhythms with a light-aligned awake-sleep cycle. As a consequence, metabolism undergoes drastic changes throughout the circadian cycle and needs plasticity to cope with opposing conditions in the day (when there is an increase in energy demands and food availability), and during the night (when prolonged fasting couples with cyclic changes in the energy demands across the sleep stages). In the last century, human behavior changed dramatically with a disregard for the natural circadian cycles. This misalignment in sleep and eating schedules strongly modulates the metabolism and energy homeostasis, favoring the development of obesity, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease (MASLD). This review summarizes the effects of circadian disruption, with a particular focus on the feeding and sleep cycles in the development of MASLD and hepatocellular carcinoma.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects two billion people worldwide and is currently mostly treatable via lifestyle interventions, such as exercise training. However, it is unclear whether the positive effects of exercise are restricted to unique circadian windows. We therefore aimed to study whether the timing of exercise training differentially modulates MASLD development. Twenty weeks old male APOE*3-Leiden.CETP mice were fed a high fat-high cholesterol diet to induce MASLD and treadmill-trained for 1 h five times per week for 12 weeks either early (ZT13; E-RUN) or late (ZT22; L-RUN) in the dark phase while corresponding sedentary groups (E-SED and L-SED) did not. Late, but not early exercise training decreased the MASLD score, body weight, fat mass, and liver triglycerides, accompanied by an altered composition of the gut microbiota. Specifically, only late exercise training increased the abundance of short-chain fatty acid-producing bacterial families and genera, such as Akkermansia, Lachnospiraceae, and Rikenella. To assess the role of the gut microbiota in training-induced effects, the study was repeated and trained (ZT22 only, RUN) or sedentary mice (SED) served as fecal donors for sedentary recipient mice (RUN FMT and SED FMT). Fecal microbiota transplantation reduced liver weight and plasma triglycerides in RUN FMT compared to SED FMT and tended to lower the MASLD score and liver triglycerides. Timing of exercise training is a critical factor for the positive effect on MASLD in this preclinical model, and the effect of late exercise is partially mediated via the gut-liver axis.

The circadian rhythm of the immune system helps to protect against pathogens1-3; however, the role of circadian rhythms in immune homeostasis is less well understood. Innate T cells are tissue-resident lymphocytes with key roles in tissue homeostasis4-7. Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations to show that innate IL-17-producing T cells-including γδ T cells, invariant natural killer T cells and mucosal-associated invariant T cells-are enriched for molecular-clock genes compared with their IFNγ-producing counterparts. We reveal that IL-17-producing γδ (γδ17) T cells, in particular, rely on the molecular clock to maintain adipose tissue homeostasis, and exhibit a robust circadian rhythm for RORγt and IL-17A across adipose depots, which peaks at night. In mice, loss of the molecular clock in the CD45 compartment (Bmal1∆Vav1) affects the production of IL-17 by adipose γδ17 T cells, but not cytokine production by αβ or IFNγ-producing γδ (γδIFNγ) T cells. Circadian IL-17 is essential for de novo lipogenesis in adipose tissue, and mice with an adipocyte-specific deficiency in IL-17 receptor C (IL-17RC) have defects in de novo lipogenesis. Whole-body metabolic analysis in vivo shows that Il17a-/-Il17f-/- mice (which lack expression of IL-17A and IL-17F) have defects in their circadian rhythm for de novo lipogenesis, which results in disruptions to their whole-body metabolic rhythm and core-body-temperature rhythm. This study identifies a crucial role for IL-17 in whole-body metabolic homeostasis and shows that de novo lipogenesis is a major target of IL-17.

Exposure to artificial light during the night is known to promote disruption to the biological clock, which can lead to impaired mood and metabolism. Metabolic hormone secretion is modulated by the circadian pacemaker and recent research has shown that hormones such as insulin and leptin can also directly affect behavioral outcomes and the circadian clock. In turn, obesity itself is known to modulate the circadian rhythm and alter emotionality. This study investigated the behavioral and metabolic effects of constant light exposure in two models of obesity - a leptin null mutant (OB) and diet-induced obesity via high-fat diet. For both experiments, mice were placed into either a standard Light:Dark cycle (LD) or constant light (LL) and their circadian locomotor rhythms were continuously monitored. After 10 weeks of exposure to their respective lighting conditions, all mice were subjected to an open field assay to assess their explorative behaviors. Their metabolic hormone levels and inflammation levels were also measured. Behaviorally, exposure to constant light led to increased period lengthening and open field activity in the lean mice compared to both obesity models. Metabolically, LL led to increased cytokine levels and poorer metabolic outcomes in both lean and obese mice, sometimes exacerbating the metabolic issues in the obese mice, independent of weight gain. This study illustrates that LL can produce altered behavioral and physiological outcomes, even in lean mice. These results also indicate that obesity induced by different reasons can lead to shortened circadian rhythmicity and exploratory activity when exposed to chronic light.

Circadian rhythms are fundamental biological processes that recur approximately every 24 h, with the sleep-wake cycle or circadian behavior being a well-known example. In the field of chronobiology, mice serve as valuable model animals for studying mammalian circadian rhythms due to their genetic similarity to humans and the availability of various genetic tools for manipulation. Monitoring locomotor activity in mice provides valuable insights into the impact of various conditions or disturbances on circadian behavior. In this review, we summarized the effects of disturbance of biological rhythms on circadian behavior in mice. External factors, especially light exert a significant impact on circadian behavior. Additionally, feeding timing, food composition, ambient temperature, and physical exercise contribute to variations in the behavior of the mouse. Internal factors, including gender, age, genetic background, and clock gene mutation or deletion, are effective as well. Understanding the effects of circadian disturbances on murine behavior is essential for gaining insights into the underlying mechanisms of circadian regulation and developing potential therapeutic interventions for circadian-related disorders in humans.

Circadian rhythm is critical to maintaining the whole-body metabolic homeostasis of an organism. Chronic disruption of circadian rhythm by shift work is an important risk factor for metabolic diseases. Fibroblast growth factor 15/19 (FGF15/19), a key component in the liver-gut axis, potently suppresses bile acid (BA) synthesis and improves insulin sensitivity. FGF15/19 emerges as a novel pharmaceutical target for prevention and treatment of metabolic diseases. The nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) deacetylase plays an important role in the maintenance of hepatic homeostasis by linking hepatic metabolism to circadian rhythm. Here, our clinical study identified that circadian rhythmicity and levels of plasma FGF19 and BA profiling, and cellular NAD+-dependent SIRT1 signaling were disturbed in night shift (NS, n = 10) compared to day shift (DS, n = 12) nurses. Our in vitro data showed that recombinant FGF19 protein rescued cellular circadian rhythm disrupted by SIRT1 inhibitors. Furthermore, we determined the effect of FGF15 on circadian rhythm and hepatic metabolism in wild-type (WT), Fgf15 knockout (KO), and Fgf15 transgenic (TG) mice. The expressions of circadian-controlled genes (CCGs) involved in SIRT1 signaling, BA and lipid metabolism, and inflammation were disrupted in Fgf15 KO compared to WT and/or Fgf15 TG mice. Moreover, systemic FGF15 deficiency led to the circadian disturbance of NAD+-dependent SIRT1 signaling and significant reduction during nighttime in mice. These findings suggest that FGF15/19 regulates the circadian energy metabolism, which warrants further studies as a putative prognostic biomarker and pharmaceutical target for preventing against metabolic diseases associated with chronic shift work.

The circadian clock gene system plays a pivotal role in coordinating the daily rhythms of most metabolic processes. It is synchronized with the light-dark cycle and the eating-fasting schedule. Notably, the interaction between meal timing and circadian clock genes (CGs) allows for optimizing metabolic processes at specific times of the day. Breakfast has a powerful resetting effect on the CG network. A misaligned meal pattern, such as skipping breakfast, can lead to a discordance between meal timing and the endogenous CGs, and is associated with obesity and T2D. Conversely, concentrating most calories and carbohydrates (CH) in the early hours of the day upregulates metabolic CG expression, thus promoting improved weight loss and glycemic control. Recently, it was revealed that microorganisms in the gastrointestinal tract, known as the gut microbiome (GM), and its derived metabolites display daily oscillation, and play a critical role in energy and glucose metabolism. The timing of meal intake coordinates the oscillation of GM and GM-derived metabolites, which in turn influences CG expression, playing a crucial role in the metabolic response to food intake. An imbalance in the gut microbiota (dysbiosis) can also reciprocally disrupt CG rhythms. Evidence suggests that misaligned meal timing may cause such disruptions and can lead to obesity and hyperglycemia. This manuscript focuses on the reciprocal interaction between meal timing, GM oscillation, and circadian CG rhythms. It will also review studies demonstrating how aligning meal timing with the circadian clock can reset and synchronize CG rhythms and GM oscillations. This synchronization can facilitate weight loss and improve glycemic control in obesity and those with T2D.

The hepatic vagal nerve mediates the impact of circadian disruption on food intake in mice.

Circadian desynchrony induced by shiftwork or jet lag is detrimental to metabolic health, but how synchronous or desynchronous signals are transmitted among tissues is unknown. We report that liver molecular clock dysfunction is signaled to the brain through the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a homeostatic feedback signal that relies on communication between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a potential therapeutic target for obesity in the setting of chronodisruption.