Ionizing radiation-induced intestinal injury (IRIII) is a catastrophic disease lack of sufficient medical countermeasures currently. Regulation of the gut microbiota through dietary adjustments is a potential strategy to mitigate IRIII. Time-restricted feeding (TRF) is an emerging behavioral nutrition intervention with pleiotropic health benefits. Whether this dietary pattern influences the pathogenesis of IRIII remains vague. We evaluated the impact of TRF on intestinal radiosensitivity in this study and discovered that only daytime TRF (DTRF), not nighttime TRF, could ameliorate intestinal damage in mice that received a high dose of IR. Faecal metagenomic and metabolomic studies revealed that the intestinal creatine level was increased by approximate 9 times by DTRF, to which the Bifidobacterium pseudolongum enrichment contribute. Further investigations showed that creatine could activate the energy sensor AMP-activated protein kinase in irradiated enterocytes and induce phosphorylation of acetyl-CoA carboxylase, resulting in reduced production of polyunsaturated fatty acids and reduced ferroptosis after IR. The administration of creatine mitigated IRIII and reduced bacteremia and proinflammatory responses. Blockade of creatine import compromised the ferroptosis inhibition and mitigation of DTRF on IRIII. Our study demonstrates a radioprotective dietary mode that can reshape the gut microbiota and increase intestinal creatine, which can suppress IR-induced ferroptosis, thereby providing effective countermeasures for IRIII prevention.

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.

This Obesity Medicine Association (OMA) Expert Joint Perspective examines steatotic liver disease (SLD), which is composed of metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) in children with obesity. The prevalence of obesity is increasing, rates have tripled since 1963 from 5 % to now 19 % of US children affected in 2018. MASLD, is the most common liver disease seen in children, can be a precursor to the development of Type 2 Diabetes (T2DM) and is the primary reason for liver transplant listing in young adults. We must be vigilant in prevention and treatment of MASLD in childhood to prevent further progression.

This joint clinical perspective is based upon scientific evidence, peer and clinical expertise. The medical literature was reviewed via PubMed search and appropriate articles were included in this review. This work was formulated from the collaboration of eight hepatologists/gastroenterologists with MASLD expertise and two physicians from the OMA.

The authors who are experts in the field, determined sentinel questions often asked by clinicians regarding MASLD in children with obesity. They created a consensus and clinical guideline for clinicians on the screening, diagnosis, and treatment of MASLD associated with obesity in children.

Obesity and the comorbidity of MASLD is increasing in children, and this is a medical problem that needs to be addressed urgently. It is well known that children with metabolic associated chronic disease often continue to have these chronic diseases as adults, which leads to reduced life expectancy, quality of life, and increasing healthcare needs and financial burden. The authors of this paper recommend healthy weight reduction not only through lifestyle modification but through obesity pharmacotherapy and bariatric surgery. Therefore, this guidance reviews available therapies to achieve healthy weight reduction and reverse MASLD to prevent progressive liver fibrosis, and metabolic disease.

A growing part of the human population is affected by circadian misalignment caused by deregulated sleep, increased nighttime light exposure and erratic eating patterns. Thus, circadian rhythms are a key research area, with compelling links to cancer. Here, we review the circadian regulation of critical cellular processes, including immunity, metabolism, cell cycle control and DNA repair, under physiological homeostasis and in cancer. We discuss the divergent evidence indicating tissue-specific roles of the circadian clock in different cancer types and the potential link between circadian misalignment and early-onset cancers. Finally, we outline how understanding the circadian clock can improve cancer prevention and chronomedicine-based therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern linked to the increasing prevalence of metabolic syndrome, including obesity and type 2 diabetes (T2D). MASLD remains a significant clinical challenge due to the absence of effective therapeutic interventions. Intermittent fasting (IF) has emerged as a promising non-pharmacological strategy for managing MASLD. Although the exact mechanisms underpinning the possible beneficial effects of IF on MASLD are not yet fully elucidated, the gut microbiota and its metabolic byproducts are increasingly recognized as potential mediators of these effects. The gut-liver axis may act as an important conduit through which IF exerts its beneficial influence on hepatic function. This review comprehensively examines the impact of various IF protocols on gut microbiota composition, investigating the resultant alterations in microbial diversity and metabolomic profiles, and their potential implications for liver health and the improvement of MASLD.

In mammals, the core molecular clock genes and the overall circadian system are established during early development; during this critical period of development, maternal metabolic condition plays a major role in programming temporal metabolic regulation. Therefore, this study aimed to evaluate the effects of the chronic maternal intake of a high-fat and high-carbohydrate diet (HFCD) before and during pregnancy, in addition to a challenge with HFCD during adulthood, on offspring diurnal metabolic profile and on clock gene expression in central and peripheral circadian oscillators. The HFCD offspring and/or those exposed to the metabolic challenge exhibited alterations in the temporal profiles of analytes associated with both the carbohydrate and lipid metabolisms, as well as markers associated with liver and kidney damage, ranging from phase changes in rhythmicity or, in some cases, to the complete loss of 24 h variations. At the molecular level, the expression of clock genes (Per1, Cry1, Bmal1, and Clock) in the central and peripheral oscillators showed differential susceptibility to undergoing changes in their abundance. Our data indicate that maternal HFCD during pregnancy, a second exposure in adulthood, or both result in the long-term misalignment of the diurnal rhythm's metabolic and damage markers; these changes are possibly associated with alterations in the core molecular circadian clockwork.

The circadian system maintains optimal biological functions at the appropriate time of day, and the disruption of this organization can contribute to the pathogenesis of cardiometabolic disorders. The timing of eating is a prominent external time cue that influences the circadian system. "Chrononutrition" is an emerging dimension of nutrition and active area of research that examines how timing-related aspects of eating and nutrition impact circadian rhythms, biological processes, and disease pathogenesis. There is evidence to support chrononutrition as a form of chronotherapy, such that optimizing the timing of eating may serve as an actionable strategy to improve cardiometabolic health. This report summarizes key information from the National Heart, Lung, and Blood Institute's virtual workshop entitled "Chrononutrition: Elucidating the Role of Circadian Biology and Meal Timing in Cardiometabolic Health," which convened on May 2 to 3, 2023, to review current literature and identify critical knowledge gaps and research opportunities. The speakers presented evidence highlighting the impact on cardiometabolic health of earlier and shorter eating windows and more consistent day-to-day eating patterns. The multidimensionality of chrononutrition was a common theme, as it encompasses multiple facets of eating along with the timing of other behaviors including sleep and physical activity. Advancing the emerging field of chrononutrition will require: (1) standardization of terminology and metrics; (2) scalable and precise tools for real-world settings; (3) consideration of individual differences that may act as effect modifiers; and (4) deeper understanding of social, behavioral, and cultural influences. Ultimately, there is great potential for circadian-based dietary interventions to improve cardiometabolic health.

The timing of dietary total fat intake influences glucose homeostasis, however, the impact of unsaturated fat (USFA) intake has yet to be explored. This 12-week, double-blind, randomized, controlled, 2 × 2 factorial-designed feeding trial investigated the effects of timing (lunch or dinner) and types of dietary USFA (high monounsaturated fat or polyunsaturated fat diet) intake on glucose metabolism in seventy prediabetes participants (mean age, 57 years). Sixty participants with completed fecal samples were included in the final analysis (n = 15 for each group). Postprandial serum glucose was first primary outcome, postprandial insulin levels and insulin sensitivity indices were co-primary outcomes Secondary outcomes were continuous glucose levels, serum fatty acid profile, gut microbiome (metagenomic sequencing) and fecal metabolites. Results showed no significant differences in postprandial glucose between groups. However, USFA intake at lunch (vs. dinner) improved insulin sensitivity and reduced postprandial insulin and serum free saturated fatty acid (Ptiming < 0.05, Ptype > 0.05, Pinteraction > 0.05), which was associated with alterations in gut microbiome and bile acid metabolism, regardless of USFA type. In summary, these results suggest that advancing timing of USFA intake improves insulin sensitivity through the gut microbiome and bile acid metabolism. Trial registration: ChiCTR2100045645.

Exercise interventions represent an effective strategy to prevent and treat metabolic diseases and the time-of-day-dependent effects of exercise on metabolic outcomes are becoming increasingly apparent. We aimed to study the influence of time-restricted wheel running on whole-body energy and glucose homeostasis. Male, 8-week-old, C57BL/6NTac mice were fed either a 60% high-fat diet (HFD) or a 10% low-fat diet (LFD) for 4 weeks. Following this, mice were given access to a running wheel between zeitgeber time (ZT) 12-16 (early dark phase) or ZT 20-0 (late dark phase). Sedentary mice had access to a permanently locked wheel. Mice were housed under these conditions in metabolic chambers for 4 weeks in which LFD and HFD conditions were maintained. Following the exercise intervention, body composition and glucose tolerance were assessed. Wheel running during either the early or late dark phase resulted in metabolic improvements such as attenuation in body weight gain, enhanced glucose tolerance and reduced ectopic lipid deposition. However, late dark phase exercise resulted in a greater reduction in body weight gain, as well as enhanced metabolic flexibility and insulin sensitivity. Our data suggest that late dark phase versus early dark phase exercise confers greater metabolic adaptations in HFD-fed mice.

Circadian Syndrome (CircS) was recently recognized as a novel predictor of cardiovascular disease (CVD) risk, with reproductive factors playing an important role in CVD risk. Yet, studies linking reproductive factors to CircS remain sparse. Data on middle-aged and elderly women were extracted from three nationally representative surveys: the China Health and Retirement Longitudinal Study (CHARLS) and the English Longitudinal Study on Ageing (ELSA) provided the training set, and the National Health and Nutrition Examination Survey (NHANES) constituted the validation set. We employed logistic regression to evaluate the association between self-reported reproductive factors and CircS risk, with inverse probability of treatment weighting (IPTW) and subgroup analyses conducted to verify the stability. A total of 11,721 participants were analyzed. CircS prevalence differed significantly across countries, with 51.40 % in China and 20.19 % in the United Kingdom. Early menarche (age <12 years) correlated with increased CircS risk in CHARLS (OR 1.38 [95 % CI 0.99-1.92]; p = 0.061), ELSA (OR 1.64 [95 % CI 1.36-1.98]; p < 0.001), and NHANES (OR1.52 [95 % CI: 1.21-1.89]; p < 0.001). Premature menopause (age <40 years) was associated with a roughly 30 % higher CircS risk. A shorter reproductive lifespan was significantly linked to CircS, with this relationship emerging at a reproductive lifespan of ≥40 years in CHARLS (OR1.39 [95 % CI: 1.04-1.84]; p = 0.024). The aforementioned correlations retained significance following IPTW and subgroup analyses. Early menarche, premature menopause, and abbreviated reproductive lifespans may negatively affect CircS. Public health strategies should incorporate menstrual cycle-related reproductive health into primary CircS prevention.

To evaluate the molecular mechanisms involved in intermittent fasting 16/8 (16/8 IF), a widespread dietary practice adopted worldwide that consists of 16 h of fasting and 8 h of feeding.

Obese mice were fasted daily from 6 am to 10 pm. Food intake, body weight, and energy expenditure were measured. Molecular mechanisms were investigated using ELISA, western blot, and qPCR of white and brown adipose tissues. Glucose homeostasis was also evaluated. Ucp1 knockout and ob/ob mice were utilized.

The 16/8 IF regimen improved glucose homeostasis and reduced body weight, food intake, and overall adiposity. Postprandial VO2, heat production, brown adipose tissue (BAT) temperature, and ketone bodies increased with 16/8 IF. Postprandial thermogenesis induced by 16/8 IF was abolished in mice after BAT denervation or Ucp1 deletion. Serum leptin levels were elevated, and most metabolic effects of 16/8 IF were absent in leptin-deficient ob/ob mice. Additionally, leptin sensitivity increased in mice exposed to 16/8 IF.

The 16/8 IF regimen can improve metabolism, with findings underscoring the role of enhanced leptin action in inhibiting food intake and promoting postprandial thermogenesis during 16/8 IF.

The physiological changes inherent to the climacteric period can trigger or aggravate overweight/obesity, among several other health disorders. This study aimed to evaluate the effects of time-restricted eating (TRE) on body composition and cardiometabolic parameters in climacteric women with obesity submitted to caloric restriction (CR) through a hypocaloric diet.

We conducted an analysis of a clinical trial in a pre-post design that included adult climacteric women with obesity. Participants were divided into two groups: hypocaloric diet control group (n = 30) - with hypocaloric diet and free meal times, and hypocaloric diet and time-restricted eating group (HTRE) (n = 27) - with hypocaloric diet and TRE (fasting from 7  pm to 7  am ), for 10 weeks. Anthropometric and biochemical parameters were evaluated before and after the intervention period. A significance level of P  < 0.05 was considered for all cases.

Both groups showed a reduction in all anthropometric parameters, but without significant difference ( P  = 0.34) between groups. However, some metabolic parameters were significantly highlighted in the HTRE such as cholesterol level normalization (HTRE, 181.76 ± 34.20 mg/dL) and a decrease in plasma atherogenicity ( P  = 0.02), glycated hemoglobin ( P  < 0.001), estimated mean glucose ( P  = 0.02), and alanine aminotransferase ( P  = 0.02), unlike the hypocaloric diet control group, which did not show such significance.

In this study, from the perspective of body composition, similar changes were observed between the group subjected to CR alone and the group subjected to CR combined with a 12-hour overnight fast. However, there was an indication of superior improvement in glycemic and lipid parameters in the group subjected to the 12-hour overnight fast. These findings suggest the potential for TRE, as implemented, to have positive effects on reducing cardiovascular risk and other chronic metabolic diseases.

This randomized controlled study sought to determine the effect of intermittent fasting on anthropometric measurements, fibroblast growth factor (FGF)-21, and autophagy markers, as well as on hepatic steatosis and fibrosis levels in overweight or obese patients with metabolic dysfunction-associated fatty liver disease (MAFLD).

Patients were randomly assigned into two groups: received a dietary treatment involving 22-25 kcal/kg/day of energy for 8 weeks and followed the same dietary intervention and a 16:8 pattern. The extent of hepatic steatosis and fibrosis was determined using transient elastography on a FibroScan® device. The controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), determined by transient elastography, reflect hepatic steatosis and fibrosis, respectively. In duplicate, serum levels of FGF-21, Beclin-1, and ATG-5 were determined using enzyme-linked immunosorbent assay.

The study included 48 patients with a mean age of 48.2 ± 1.4 years (27 female and 21 male). Improvements in anthropometric measurement and CAP and LSM levels and a decrease in serum FGF-21 levels were found in both groups (p < 0.05). Changes in the CAP and FGF-21 levels were higher in the energy + time-restricted diet group (p < 0.05). Autophagy-related protein (ATG)-5 levels increased only in the energy + time-restricted diet group [(0.74 (0.46-1.29) ng/mL vs. 0.95 (0.73-1.32) ng/mL, p = 0.03].

Intermittent fasting was potentially practical in the management of MAFLD. In particular, changes in FGF-21 and ATG-5 levels indicate the potential of intermittent fasting to regulate metabolic processes and autophagy. However, methodological limitations should be taken into consideration when interpreting the study results.

Autologous fat grafting confronts challenges of inconsistent retention and complications. Intermittent fasting (IF), an emerging dietary management strategy, shows potential in tissue repair and fat metabolism, and yet to know in fat grafting.

The aim of this study is to address the impact of 16:8 IF on the outcome of fat grafting in mice.

Male C57BL/6 mice were randomly assigned to postoperative IF regimen group (n = 24) and ad libitum group with unrestricted feeding (n = 24). For postoperative IF group, animals were put on a feeding schedule with 8 hours of unrestricted access to standard diet per day followed by 16-h fasting period after fat grafting. Fat grafts were harvested at 2, 4 and 12 weeks postoperatively. We addressed the mass retention and graft quality through weighting and ultrasound examination. Histological remodeling of fat grafts was evaluated by Masson staining and immunofluorescence staining.

In comparison with unrestricted feeding, postoperative IF strategies improved the mass retention of fat grafts, and optimized the outcomes characterized by enhanced adipogenesis, accelerated revascularization, facilitated M2 macrophage infiltration as well as reduced fibrosis and oil cyst formation.

Postoperative IF improved the retention and outcomes of fat grafting in mice, and could be suggested as a dietary intervention strategy after fat grafting clinically.

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High-intensity interval training (HIIT) and time-restricted feeding (TRF) have shown promise for improving glucose regulation by increasing insulin sensitivity, enhancing glucose uptake, reducing glucose production. Therefore, this study investigates the combined effects of HIIT and TRF on the AKT/FOXO1/PEPCK signaling pathway in the liver tissue of type 2 diabetic rats. 42 male Wistar rats (4-5 weeks of age) were included in the study. The animals were randomly divided into two groups: (1) Standard diet (SD, non-Diabetic (Non-D, n = 7) (2) High-fat diet (HFD, n = 35) for 4 weeks. To induce diabetes, 35 mg/kg of streptozotocin (STZ) was injected intraperitoneally (IP). Animals with blood glucose levels of > 250 mg/dL were considered as diabetic. Diabetic rats were randomly divided into 5 groups (n = 7): (1) Diabetes-exercise (D-EX), (2) Diabetes-TRF (D-TRF), (3) Diabetes-combined TRF and exercise (D-TRF&EX), (4) Diabetes no treatment (D-NT), (5) Diabetes with metformin (D-MET). Interventions (HIIT and TRF) were performed for 10 weeks. Rats in the Non-D group did not exercise and did not receive metformin or TRF. Periodic Acid-Schiff (PAS) staining was used to histologically analyze the liver tissue. Levels of blood glucose, insulin resistance (IR), FOXO1 protein, PEPCK, and area under the curve (AUC) following the IPGTT test, were significantly decreased in treatment groups compared to the D-NT group (p < 0.05). The AKT protein levels (p < 0.01), glycogen content (p < 0.05), and insulin sensitivity (p < 0.001) increased in the treatment groups as compared with the D-NT group. Microscopic examination of the liver tissue in general showed a better tissue arrangement in both treatment groups than in the D-NT group. Combining HIIT and TRF may be effective for improving blood glucose regulation, insulin sensitivity, in type 2 diabetes, as compared to TRF or HIIT interventions alone.

Background/Objectives: High-intensity interval training (HIIT) and time-restricted feeding (TRF) have shown potential in enhancing glucose metabolism, increasing insulin sensitivity, and promoting muscle health. This study investigates the combined effects of HIIT and TRF on the AKT-IGF-1-mTOR signaling pathway in the muscle tissue of type 2 diabetic (T2D) rats. Methods: 42 male Wistar rats (4-5 weeks of age) were included in the study. The animals were randomly divided into two groups: 1. Standard diet (SD) non-diabetic (n = 7) and 2. High-fat diet (HFD n = 35) for 4 weeks. T2D was induced by intraperitoneal injection (IP) of streptozotocin (STZ) at 35 mg/kg. Animals with blood glucose levels ≥ 250 mg/dL were considered diabetic. Diabetic rats were randomly divided into five groups (n = 7): 1. Diabetes-HIIT (D-HIIT), 2. Diabetes-TRF (D-T), 3. Diabetes-combined TRF and HIIT (D-T+HIIT), 4. Diabetes-Untreated Control (D), and 5. Diabetes with metformin (D-MET). The HIIT protocol and TRF regimen were followed for 10 weeks. Muscle tissue was collected for histological analysis, and the expression of proteins related to the AKT-IGF-1-mTOR pathway was measured. Results: Blood glucose levels, insulin resistance (IR), and markers of muscle degradation were significantly improved in the D-T+HIIT and D-MET groups compared to the non-diabetes group. Furthermore, the activation of the AKT and mTOR signaling proteins, as well as increased IGF-1 expression, was significantly elevated in the D-T+HIIT group compared to the diabetic control group and other treatment groups, and approached levels observed in the non-diabetes group. Additionally, muscle fiber size and overall tissue structure were improved in the treatment groups, particularly in the D-T+HIIT group. Conclusions: The combination of HIIT and TRF appears to offer superior benefits in improving muscle protein synthesis, and glucose regulation in T2D rats, as compared to either HIIT or TRF alone. These findings highlight the potential of this combined approach for addressing muscle-related complications in T2D.

Most aspects of physiology and behaviour fluctuate every 24 h in mammals. These circadian rhythms are orchestrated by an autonomous central clock located in the suprachiasmatic nuclei that coordinates the timing of cellular clocks in tissues throughout the body. The critical role of this circadian system is emphasized by increasing evidence associating disruption of circadian rhythms with diverse pathologies. Accordingly, mounting evidence suggests a bidirectional relationship where disruption of rhythms by circadian misalignment may contribute to liver diseases while liver diseases alter the central clock and circadian rhythms in other tissues. Therefore, liver pathophysiology may broadly impact the circadian system and may provide a mechanistic framework for understanding and targeting metabolic diseases and adjust metabolic setpoints.

Sleep loss dysregulates cellular metabolism and energy homeostasis. Highly metabolically active cells, such as neurons, enter a catabolic state during periods of sleep loss, which consequently disrupts physiological functioning. Specific to the central nervous system, sleep loss results in impaired synaptogenesis and long-term memory, effects that are also characteristic of neurodegenerative diseases. In this review, we describe how sleep deprivation increases resting energy expenditure, leading to the development of a negative energy balance-a state with insufficient metabolic resources to support energy expenditure-in highly active cells like neurons. This disruption of energetic homeostasis alters the balance of metabolites, including adenosine, lactate, and lipid peroxides, such that energetically costly processes, such as synapse formation, are attenuated. During sleep loss, metabolically active cells shunt energetic resources away from those processes that are not acutely essential, like memory formation, to support cell survival. Ultimately, these findings characterize sleep loss as a metabolic disorder.

Time-restricted eating (TRE) helps regulate rest-activity rhythms, blood glucose, and other diurnally regulated energetics processes, which may have implications for persistent fatigue. In a randomized controlled trial, we tested the effects of TRE vs. control on fatigue in cancer survivorship.

Adult cancer survivors were recruited who were 2 months to 2 years post-treatment and reported moderate to severe fatigue. Participants were randomized 1:1, TRE:control, and all received individualized nutrition counseling. The TRE group self-selected a 10-h eating window for 12 weeks. At baseline, week 6, and week 12, participants were asked to log eating instances, complete the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire (FACIT-F, higher score = less fatigue), and wear an actigraph and continuous glucose monitor.

Thirty participants completed baseline assessments and were randomized (77% female, 53% Black/African American, 43% White, 7% Hispanic; 54.1 ± 14.7 years old; 87% with blood cancer); 25 completed 12-week assessments. TRE led to a meaningful reduction in fatigue at week 12 controlling for baseline levels (change in FACIT-F fatigue subscale = 0.0 ± 5.4 for control, 4.1 ± 5.7 for TRE, p = 0.11, effect size (ES) = 0.70; clinically meaningful threshold = 3.0 points). Glucose parameters (e.g., average interstitial glucose, average fasting glucose) tended to be lower, and rest-activity rhythms tended to indicate more regularity for those in the TRE vs. control group at weeks 6 and 12, though differences were not statistically significant (p > 0.19).

A 12-week, nutritionist-led TRE program led to less fatigue than control. Continued study of TRE patterns are warranted to optimize this eating pattern and address persistent cancer-related fatigue.

ClinicalTrials.gov Identifier: NCT05256888.

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.

Intermittent fasting (IF) and ketogenic diets (KDs) have recently attracted much attention in the scientific literature and in popular culture and follow a longer history of exercise and caloric restriction (CR) research. Whereas IF involves cyclic metabolic switching (CMS) between ketogenic and non-ketogenic states, KDs and CR may not. In this Perspective, I postulate that the beneficial effects of IF result from alternating between activation of adaptive cellular stress response pathways during the fasting period, followed by cell growth and plasticity pathways during the feeding period. Thereby, I establish the cyclic metabolic switching (CMS) theory of IF. The health benefits of IF may go beyond those seen with continuous CR or KDs without CMS owing to the unique interplay between the signalling functions of the ketone β-hydroxybutyrate, mitochondrial adaptations, reciprocal activation of autophagy and mTOR pathways, endocrine and paracrine signalling, gut microbiota, and circadian biology. The CMS theory may have important implications for future basic research, clinical trials, development of pharmacological interventions, and healthy lifestyle practices.

Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited progressive kidney disease. Time-restricted eating (TRE) is a fasting regimen that restricts eating to a particular window (typically 8 hours/day), which could slow cyst growth based on preclinical models.

A 12-month, randomized, controlled, behavioral dietary intervention compared TRE with a control group given healthy eating advice without TRE (HE), without caloric restriction. Participants underwent baseline and 12-month measurements, including adherence (percentage of participants adhering to the 8-hour window; primary outcome), and MRI to determine height-adjusted total kidney volume (htTKV) and adiposity.

Twenty-nine participants (23 females, mean standard ± deviation 48 ± 9 years) with a body mass index of 31.1±5 kg/m2 were randomized to TRE (n = 14) or HE (n = 15). Of the total participants, 71% (n = 10) of TRE and 87% (n = 13) of HE participants completed the intervention. The eating window was 9.6 ± 3.6 hours for TRE (60% achieving the 8-hour window) and 12.0 ± 2.0 for HE groups (P = .07). At month 12, both groups lost modest weight (-2.4 ± 6.4% and -3.6 ± 5.4% in the TRE and HE groups, respectively). Annual change in htTKV was 3.0 ± 8.5% and 4.6 ± 8.8% in the TRE and HE groups, respectively. Both change in weight (r = 0.67, P < .01) and change in visceral adiposity (r = 0.54, P < .01) were positively correlated with change in htTKV.

Both the TRE and HE group lost modest weight at 12 months. The targeted TRE adherence of ≥75% of participants was not achieved. Weight and adiposity loss may be more important drivers of kidney growth than the timing of eating.

The circadian clock is a transcriptional-translational feedback loop which oscillates in virtually all nucleated cells of the body. In the decades since its discovery, it has become evident that the molecular clockwork is inextricably linked to energy metabolism. Given the frequency with which metabolic dysfunction and clock disruption co-occur, understanding why and how clock and metabolic processes are reciprocally coupled will have important implications for supporting human health and wellbeing. Here, we discuss the relevance of molecular clock function in metabolic tissues and explore its role not only as a driver of day-night variation in gene expression, but as a key mechanism for maintaining metabolic homeostasis in the face of fluctuating energy supply and demand.

Overweight and obesity are linked to mitochondrial alterations, impaired glucose tolerance and a high risk of type 2 diabetes. Time-restricted eating (TRE) may aid in facilitating weight loss to prevent diabetes. Here, we investigated if TRE in individuals with overweight and prediabetes or obesity affects mitochondrial bioenergetics of peripheral blood mononuclear cells (PBMCs) and platelets using the Seahorse extracellular flux technology. In a 3-month randomized controlled trial, PBMCs/platelets were analyzed from 52 participants before and after a TRE intervention with a 10-h eating window or habitual living. PBMC and platelet respiratory function was evaluated through sequential addition of substrates, uncouplers, and inhibitors in living cells. After 3 months, there were no statistically significant differences in mitochondrial respiration within or between the TRE and control groups. Association analyses between PBMC/platelet respiration and clinical parameters including body mass index and fat mass showed no significant effects. In conclusion, 3 months of 10-h TRE does not alter the mitochondrial bioenergetics of PBMCs and platelets in individuals with high risk of type 2 diabetes.

Feeding rhythms regulate exercise performance and muscle energy metabolism. However, the mechanisms regulating adipocyte functions remain unclear. Here, using multi-omics analyses, involving (phospho-)proteomics and lipidomics, we found that day-restricted feeding (DRF) regulates diurnal rhythms of the mitochondrial proteome, neutral lipidome, and nutrient-sensing pathways in mouse gonadal white adipose tissue (GWAT). Adipocyte-specific knockdown of Prkaa2 (the gene encoding AMPKα2) impairs physical endurance. This defect is associated with altered rhythmicity in acyl-coenzyme A (CoA) metabolism-related genes, a loss of rhythmicity in the GWAT lipidome, and circadian remodeling of serum metabolites-in particular, lactate and succinate. We also found that adipocyte Prkaa2 regulates muscle clock genes during DRF. Notably, oral administration of the AMPK activator C29 increases endurance and muscle functions in a time-of-day manner, which requires intact adipocyte AMPKα2 signaling. Collectively, our work defines adipocyte AMPKα2 signaling as a critical regulator of circadian metabolic coordination between fat and muscle, thereby enhancing exercise performance.

The prevalence of type 2 diabetes (T2D) has increased significantly over the past three decades, with an estimated 30-40% of cases remaining undiagnosed. Brown and beige adipose tissues are known for their remarkable catabolic capacity, and their ability to diminish blood glucose plasma concentration. Beige adipose tissue can be differentiated from adipose-derived stem cells or through transdifferentiation from white adipocytes. However, the impact of T2D progression on beige adipocytes' functional capacity remains unclear. Transcriptomic profiling of subcutaneous adipose tissue biopsies from healthy normal-weight, obese, prediabetic obese, and obese subjects diagnosed with T2D, reveals a progressive alteration in cellular processes associated with catabolic metabolism, circadian rhythms, thermogenesis-related signaling pathways, cellular stress, and inflammation. MAX is a potential transcription factor that links inflammation with the circadian clock and thermogenesis during the progression of T2D. This study unveils an unrecognized transcriptional circuit that increasingly disrupts subcutaneous adipose tissue oxidative capacity during the progression of T2D. These findings could open new research venues for developing chrono-pharmaceutical strategies to treat and prevent T2D.

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.

Inactivation of telomerase (TERT) in adipocyte progenitor cells (APC) expedites telomere attrition, and the onset of diabetes in mice fed high-fat diet (HFD), which promotes APC over-proliferation and replicative senescence. Here, we show that time-restricted feeding or caloric restriction in the postnatal development of mice subsequently subjected to HFD prevents telomere attrition but not glucose intolerance. This metabolic effect of dietary intervention was not observed for mice with TERT KO in endothelial or myeloid cells. To characterize the telomere-independent effects of TERT in the APC lineage, we analyzed mice with TERT knockout in mature adipocytes (AD-TERT-KO), which do not proliferate and avoid telomere attrition. Analysis of adipocytes from AD-TERT-KO mice indicated reliance on glycolysis and decreased mitochondrial oxidative metabolism. We show that AD-TERT-KO mice have reduced cold tolerance and metabolism abnormality indicating a defect in adaptive thermogenesis, characteristic of aging. Conversely, ectopic TERT expression in brown adipocytes-induced mitochondrial oxidation and thermogenic gene expression. We conclude that TERT plays an important non-canonical function in the mitochondria of adipocytes.

The daily eating window significantly impacts weight and metabolic health, yet its ideal duration remains uncertain. Thirty-four healthy middle-aged women were randomly assigned to two intervention groups: 8-h time-restricted eating (TRE) and 14-h time-extended eating (EXE). Each intervention lasted 4 wk, with a 16-d washout period before switching to the other intervention. Clinical biomarkers were collected before and after each intervention, and sleep quality was assessed using the Korean Version of the Pittsburgh Sleep Quality Index (PSQI-K). Additionally, a daily visual analogue scale (VAS) was used to evaluate psychological changes. The TRE group experienced significant weight reduction, lower fasting plasma glucose and total serum cholesterol levels compared to the EXE group, but with an increase in systolic blood pressure. The EXE group showed improved blood pressure. The TRE group reported higher stress levels on the VAS, but the PSQI-K indicated improved sleep quality during the second intervention. An 8-h TRE, without calorie restriction or diet composition changes, proves more beneficial for weight management and plasma glucose control compared to the 14-h EXE among Korean women. Implementation of this approach is recommended to be gradual to mitigate psychological fluctuations and adverse blood pressure changes. The trial was registered with ClinicalTrials.gov (ID: NCT05964179) and Clinical Research Information Service (CRIS, Korea) (ID: KCT0008640).

Time-restricted feeding (TRF) is a lifestyle intervention that aims to maintain a consistent daily cycle of feeding and fasting to support robust circadian rhythms. Recently, it has gained scientific, medical, and public attention due to its potential to enhance body composition, extend lifespan, and improve overall health, as well as induce autophagy and alleviate symptoms of diseases like cardiovascular diseases, type 2 diabetes, neurodegenerative diseases, cancer, and ischemic injury. However, there is still considerable debate on the primary factors that contribute to the health benefits of TRF. Despite not imposing strict limitations on calorie intake, TRF consistently led to reductions in calorie intake. Therefore, while some studies suggest that the health benefits of TRF are primarily due to caloric restriction (CR), others argue that the key advantages of TRF arise not only from CR but also from factors like the duration of fasting, the timing of the feeding period, and alignment with circadian rhythms. To elucidate the roles and mechanisms of TRF beyond CR, this review incorporates TRF studies that did not use CR, as well as TRF studies with equivalent energy intake to CR, which addresses the previous lack of comprehensive research on TRF without CR and provides a framework for future research directions.

This review explores the complex interplay between genetic predispositions to obesity, circadian rhythms, metabolic regulation, and sleep. It highlights how genetic factors underlying obesity exacerbate metabolic dysfunction through circadian misalignment and examines promising interventions to mitigate these effects.

Genome-wide association Studies (GWAS) have identified numerous Single Nucleotide Polymorphisms (SNPs) associated with obesity traits, attributing 40-75% heritability to body mass index (BMI). These findings illuminate critical links between genetic obesity, circadian clocks, and metabolic processes. SNPs in clock-related genes influence metabolic pathways, with disruptions in circadian rhythms-driven by poor sleep hygiene or erratic eating patterns-amplifying metabolic dysfunction. Circadian clocks, synchronized with the 24-h light-dark cycle, regulate key metabolic activities, including glucose metabolism, lipid storage, and energy utilization. Genetic mutations or external disruptions, such as irregular sleep or eating habits, can destabilize circadian rhythms, promoting weight gain and metabolic disorders. Circadian misalignment in individuals with genetic predispositions to obesity disrupts the release of key metabolic hormones, such as leptin and insulin, impairing hunger regulation and fat storage. Interventions like time-restricted feeding (TRF) and structured physical activity offer promising strategies to restore circadian harmony, improve metabolic health, and mitigate obesity-related risks.

Exposure to artificial light at night (ALAN) disrupts natural darkness and desynchronizes daily rhythms in physiological processes and behavior. Previously, in rats, we have shown that dim ALAN disturbed the central circadian control and the temporal organization of behavior, and hormonal and metabolic pathways. The measurements of undisturbed daily behavioral (locomotor activity, feeding and drinking) patterns revealed reduced amplitudes and a transitory activity peak in the middle of the light (i.e. resting) period. Recent studies indicated that time-restricted feeding during the active period (TRFd) can strengthen daily rhythms and improve metabolic health. Therefore, the aim of our study was to prevent the dim ALAN-induced attenuation of daily behavioral rhythms by applying TRFd. Male Wistar rats were kept in a 12/12 light/dark cycle in metabolic cages for one week with free access to food and water. After acclimation, rats were divided into two groups: 1) ad libitum food or 2) time-restricted food during the dark period. After one week, both groups were exposed to dim ALAN for two weeks. Despite the enhanced amplitude of the daily feeding rhythm in TRFd animals, ALAN still suppressed the rhythm of locomotor activity, induced the extra peak during the resting period and reduced the bimodal pattern during the night. Furthermore, TRFd did not prevent the drop in anticipatory thirst caused by ALAN at the end of the active period. In conclusion, TRFd was not able to fully prevent the weakning of daily behavioral rhythms by dim ALAN.

Microglia, the brain's resident macrophages, are key mediators of neuroinflammation, responding to immune pathogens and toxins. They play a crucial role in clearing cellular debris, regulating synaptic plasticity, and phagocytosing amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Recent studies indicate that microglia not only exhibit intrinsic circadian rhythms but are also regulated by circadian clock genes, influencing specific functions such as phagocytosis and the modulation of neuroinflammation. Disruption of the circadian rhythm is closely associated with AD pathology. In this review, we will provide an overview of how circadian rhythms regulate microglia-mediated neuroinflammation in the progression of AD, focusing on the pathway from the central nervous system (CNS) and the peripheral immune system. We also discuss potential therapeutic targets, including hormone modulation, lifestyle interventions, and anti-inflammatory therapies, aimed at maintaining brain health in AD. This will shed light on the involvement of circadian rhythm in AD and explore new avenues for AD treatment.

Modern habits are becoming more and more disruptive to health. As our days are often filled with circadian disruption and stress exposures, we need to understand how our responses to these external stimuli are shaped and how their mediators can be targeted to promote health. A growing body of research demonstrates the role of the gut microbiota in influencing brain function and behavior. The stress response and circadian rhythms, which are essential to maintaining appropriate responses to the environment, are known to be impacted by the gut microbiota. Gut microbes have been shown to alter the host's response to stress and modulate circadian rhythmicity. Although studies demonstrated strong links between the gut microbiota, circadian rhythms and the stress response, such studies were conducted in an independent manner not conducive to understanding the interface between these factors. Due to the interconnected nature of the stress response and circadian rhythms, in this review we explore how the gut microbiota may play a role in regulating the integration of stress and circadian signals in mammals and the consequences for brain health and disease.

Time-restricted feeding (TRF) is a distinct regimen of intermittent fasting advocated for health improving. Although nighttime TRF (NRF) in rodents is analogous to daytime TRF (DRF) in humans and has health benefits, the effects of DRF on rodent's health remain uncertain. The adverse health effects of DRF in rodents are primarily attributed to its implementation-induced temporal shift in the expression of circadian rhythm-related genes. However, studies also demonstrate the health-beneficial effect of restricted feeding itself on metabolic homeostasis, particularly in periphery tissues. Moreover, the direct effects of DRF on aging progression in rodents are underexplored, highlighting a gap in current research. To explore the overall health effects of long-term DRF in rodents, especially its influence on aging progression, we investigated the impact of long-term DRF on mice under a progeric aging condition. Results showed that both 4-h and 8-h DRF regimens exerted positive effects on aging retardation; these effects were manifested as improved physical and memory capacities, enhanced liver and kidney functions, and reduced oxidative damage and inflammatory response. These DRF regimens also lowered the manifestation of aging-related markers in peripheral tissues, with decreased SA-β-gal staining and p16 expression. Mechanistically, DRF regimens, especially DRF8, upregulated AMPK signaling and downregulated mTORC1 signaling. Interestingly, the health benefits of DRF are similar to those of metformin intervention. In conclusion, our study demonstrates for the first time that DRF effectively counteracts oxidative stress-induced aging progression in mice, supporting the viewpoint that TRF as a promising strategy for preventing aging and aging-related disorders.

This study aimed to investigate the associations between evening eating and quality of energy and macronutrients and obesity among U.S. adults.

This study adopted the data from the National Health and Nutrition Examination Survey (2003-2016), which involved a total of 27,911 participants. The differences in the ratios of energy and macronutrients with it is subgroups at dinner versus breakfast (ΔRatio) were categorized into quartiles. The differences in the consumption of 17 types of food at dinner versus breakfast (ΔFoods) were considered as continuous variables. Body mass index (BMI) and waist circumference (WC) were used to define general obesity (30.0 ≤ BMI < 40.0), morbid obesity (BMI ≥ 40.0), and abdominal obesity (WC > 102 cm for men or WC > 88 cm for women). Multiple logistic and linear regression models were developed.

After a variety of covariates were adjusted, participants in the highest quartile (higher energy/macronutrient intake at dinner than breakfast) of the ΔRatio in terms of energy were positively associated with morbid obesity compared with those in the lowest quartile (ORΔRatio of energy 1.27; 95% CI 1.01;1.61) from fat (ORΔRatio of fat 1.27, 95% CI 1.01;1.60); saturated fatty acids(ORΔRatio of SFA 1.27, 95% CI 1.01;1.59) and unsaturated fatty acids (ORΔRatio of USFA 1.28, 95% CI 1.02;1.5). The highest quartile of the ΔRatio of low-quality carbohydrates was associated with increased odds of abdominal obesity (ORΔRatio of low-quality carbohydrates 1.16; 95%CI 1.03-1.31). Moreover, the ΔRatio of low-quality carbohydrates was significantly positively associated with BMI (coefficient: 0.562, 95% CI: 0.217-0.907). ΔFoods, including whole fruits, other starchy vegetables, added sugars, poultry, dairy, and nuts, were positively associated with obesity.

In conclusion, with this nationally representative sample of U.S adults, this study demonstrated that excessive intake of energy at dinner than breakfast during a day was associated with a greater risk of obesity, mainly from low-quality carbohydrates, fat, SFAs, and USFA. This study emphasized the importance of diet quality and evening eating in the prevention of obesity.