Time-restricted feeding downregulates cholesterol biosynthesis program via RORγ-mediated chromatin modification in porcine liver organoids

Background: Time-restricted feeding(TRF) is a dieting strategy based on nutrients availability and diurnal rhythm,shown to improve lipid metabolism efficiency. We have demonstrated previously that retinoic acid-related(RAR)orphan receptor(ROR) γ is the primary transcription factor controlling cholesterol(CHO) biosynthesis program of animals. However, the functional role of RORγ in liver physiology of pigs in response to TRF has not been determined, largely due to the lack of functional models and molecular tools. In the present study, we established porcine liver organoids and subjected them to restricted nutrients supply for 10-h during the light portion of the day.Results: Our results showed that TRF regimen did not alter hepatocyte physiology, including unchanged cell viability, caspase 3/7 enzyme activity and the gene signature of cell proliferation in porcine liver organoids,compared to the control group(P > 0.05). Furthermore, we found that TRF downregulated the hepatic CHO biosynthesis program at both mRNA and protein levels, along with the reduced cellular CHO content in porcine liver organoids(P < 0.05). Using unbiased bioinformatic analysis of a previous ChIP-seq data and ChIP-qPCR validation, we revealed RORγ as the predominant transcription factor that responded to TRF, amongst the 12 targeted nuclear receptors(NRs)(P < 0.05). This was likely through RORγ direct binding to the MVK gene(encoding mevalonate kinase). Finally, we showed that RORγ agonists and overexpression enhanced the enrichment of cofactor p300, histone marks H3 K27 ac and H3K4me1/2, as well as RNA polymerase II(Pol-II) at the locus of MVK, in TRF-porcine liver organoids, compared to TRF-vector control(P < 0.05).Conclusions: Our findings demonstrate that TRF triggers the RORγ-mediated chromatin remodeling at the locus of CHO biosynthesis genes in porcine liver organoids and further improves lipid metabolism.

Effects of time-restricted eating with different eating duration on anthropometrics and cardiometabolic health:A systematic review and meta-analysis

BACKGROUND Time-restricted eating(TRE)is a dietary approach that limits eating to a set number of hours per day.Human studies on the effects of TRE intervention on cardiometabolic health have been contradictory.Heterogeneity in subjects and TRE interventions have led to inconsistency in results.Furthermore,the impact of the duration of eating/fasting in the TRE approach has yet to be fully explored.AIM To analyze the existing literature on the effects of TRE with different eating durations on anthropometrics and cardiometabolic health markers in adults with excessive weight and obesity-related metabolic diseases.METHODS We reviewed a series of prominent scientific databases,including Medline,Scopus,Web of Science,Academic Search Complete,and Cochrane Library articles to identify published clinical trials on daily TRE in adults with excessive weight and obesity-related metabolic diseases.Randomized controlled trials were assessed for methodological rigor and risk of bias using version 2 of the Cochrane risk-of-bias tool for randomized trials(RoB-2).Outcomes of interest include body weight,waist circumference,fat mass,lean body mass,fasting glucose,insulin,HbA1c,homeostasis model assessment for insulin resistance(HOMA-IR),lipid profiles,C-reactive protein,blood pressure,and heart rate.RESULTS Fifteen studies were included in our systematic review.TRE significantly reduces body weight,waist circumference,fat mass,lean body mass,blood glucose,insulin,and triglyceride.However,no significant changes were observed in HbA1c,HOMA-IR,total cholesterol,low-density lipoprotein cholesterol,high-density lipoprotein cholesterol,heart rate,systolic and diastolic blood pressure.Furthermore,subgroup analyses based on the duration of the eating window revealed significant variation in the effects of TRE intervention depending on the length of the eating window.CONCLUSION TRE is a promising chrononutrition-based dietary approach for improving anthropometric and cardiometabolic health.However,further clinical trials are needed to determine the optimal eating duration in TRE intervention for cardiovascular disease prevention.

Potential preventive effects of time-restricted eating on cancer

Intermittent fasting is a novel dietary intervention that has been demonstrated to improve the efficacy of cancer therapy and reduce complications.Time-restricted eating is a specific form of intermittent fasting.It usually restricts only the daily eating window and not the amount of calories consumed.In addition to providing a means for weight management and improving metabolism like other intermittent fasting methods,time-restricted eating also synchronizes circadian rhythms and affects autophagy levels,which has potential antiaging effects.Some studies have shown that time-restricted eating can prevent tumorigenesis and slow tumor progression.Moreover,because of its simplicity and mild adverse effects,time-restricted eating is safe and has a high rate of compliance.It may be used an adjuvant therapy and may be part of a healthy lifestyle suitable for long term by cancer patients or those at high risk of developing specific cancers.This article expounds on the potential impact of time-restricted eating on the prevention and treatment of cancer,as well as the potential mechanism(s)of action.There are 3 main aspects considered to be impacted by time-restricted eating:improving obesity and metabolic disorders,synchronizing the circadian rhythm,and upregulating autophagy.We herein present the current research progress related to the effects of time-restricted eating on malignant tumors.The purpose of this review is to provide a theoretical basis and direction for future research to explore the potential of time-restricted eating as a nutritional intervention to prevent the occurrence of cancer and as a treatment or adjuvant therapy for cancer.We believe that this approach may be conducive to improving the nutritional status of cancer patients and improving their prognosis and quality of life.

Relative Time-Restricted Sensitivity and Entropy

In this paper,we consider relativization of measure-theoretical-restricted sensitivity.For a given topological dynamical system,we define conditional measure-theoretical-restricted asymptotic rate with respect to sensitivity and obtain that it equals to the reciprocal of the Brin–Katok local entropy for almost every point under the conditional measure.

Impaired function of the suprachiasmatic nucleus rescues the loss of body temperature homeostasis caused by time-restricted feeding

The suprachiasmatic nucleus(SCN)is the master circadian pacemaker that drives body temperature rhythm.Time-restricted feeding(TRF)has potential as a preventative or therapeutic approach against many diseases.The potential side effects of TRF remain unknown.Here we show that daily 4-h TRF treatment in mice can severely impair body temperature homeostasis and can result in lethality.Nearly half of the mice died at 21℃,and all mice died at 18℃during 4-h TRF.This effect was modulated by the circadian clock and was associated with severe hypothermia due to loss of body temperature homeostasis.Remarkably,disrupting the circadian clock by SCN lesions or constant light rescued lethality during TRF.Analysis of circadian gene expression in the dorsomedial hypothalamus(DMH)demonstrated that TRF reprograms rhythmic transcriptome in DMH and suppresses expression of genes,such as Ccr5 and Calcrl,which are involved in thermoregulation.Together,our results demonstrated a potent effect of TRF on body temperature homeostasis and the role of SCN function in this process.Our results further suggested that circadian arrhythmicity can have potential beneficial effects under certain stress conditions.

Time-restricted feeding:what we have done and what more we can do?

Obesity and other metabolic syndromes such as hypertension,type 2 diabetes,and hyperlipidemia remain a major public health burden worldwide.Apart from higher incidence of cardiovascular diseases,obesity and other abnormal metabolic status also promote cancer development and poor prognosis of cancer patients(1-3).In addition to using different surgical modalities(4),weight management through lifestyle changes has proven to be a more economical and low-risk approach.For obese patients,whether daily caloric intake can be reasonably restricted is recognized as an important strategy for solving their problem.In the past few years,intermittent fasting(IF),especially time-restricted feeding(TRF),has shown good clinical weight loss effect(>5%loss from baseline)(5).Moreover,people who participate in IF or TRF can often show good compliance,because compared with traditional dieting,IF or TRF does not require participants to record the specific calories of each meal in detail,participants only need to eat within the specified time period and not have any caloric intake at any other time.