{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:56:28Z","timestamp":1792626988108,"version":"4.5.0"},"reference-count":55,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010877","name":"Shenzhen Science and Technology Innovation Commission","doi-asserted-by":"crossref","award":["JCYJ20210324094010029"],"award-info":[{"award-number":["JCYJ20210324094010029"]}],"id":[{"id":"10.13039\/501100010877","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100010877","name":"Shenzhen Science and Technology Innovation Commission","doi-asserted-by":"crossref","award":["JCYJ20220531100811026"],"award-info":[{"award-number":["JCYJ20220531100811026"]}],"id":[{"id":"10.13039\/501100010877","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shenzhen Science and Technology Program","award":["KQTD20240729102249044"],"award-info":[{"award-number":["KQTD20240729102249044"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) is closely linked to metabolic syndrome and circadian rhythm disruption, yet the mechanisms by which lifestyle interventions restore circadian organization remain incompletely understood. In this study, we employed a stringent 3 h time-restricted feeding (TRF) regimen in a mouse model of high-fat diet (HFD)-induced metabolic dysfunction. TRF markedly improved metabolic outcomes, including lipid accumulation, glucose tolerance, and behavioral and physiological rhythms. Importantly, through transcriptomic profiling using RNA sequencing, we found that TRF induced circadian rhythmicity in previously arrhythmic hepatic genes. This approach revealed that TRF promotes transcriptional synchronization within key metabolic pathways. Genes involved in autophagy, fatty acid metabolism, and protein catabolism exhibited coherent peak expression at defined time windows, suggesting that TRF temporally restructures gene networks to enhance metabolic efficiency. This intra-pathway synchronization likely minimizes energy waste and enables cells to execute specialized functions in a temporally optimized manner. Together, our findings identify temporal reorganization of metabolic pathways as a mechanistic basis for the benefits of TRF, providing new insight into circadian-based strategies for managing metabolic disease.<\/jats:p>","DOI":"10.3390\/cells15020193","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T13:02:07Z","timestamp":1768914127000},"page":"193","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synchronizing the Liver Clock: Time-Restricted Feeding Aligns Rhythmic Gene Expression in Key Metabolic Pathways"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1958-505X","authenticated-orcid":false,"given":"Shiyan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5407-1503","authenticated-orcid":false,"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6378-1131","authenticated-orcid":false,"given":"Yiming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailin","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/hep.29724","article-title":"Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"68","author":"Younossi","year":"2018","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1001\/jama.2015.5370","article-title":"Nonalcoholic fatty liver disease: A systematic review","volume":"313","author":"Rinella","year":"2015","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.cmet.2015.08.006","article-title":"Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness","volume":"22","author":"Jacobi","year":"2015","journal-title":"Cell Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"C1158","DOI":"10.1152\/ajpcell.00551.2022","article-title":"Circadian regulation of liver metabolism: Experimental approaches in human, rodent, and cellular models","volume":"325","author":"Daniels","year":"2023","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e52412","DOI":"10.15252\/embr.202152412","article-title":"Nutrition, metabolism, and epigenetics: Pathways of circadian reprogramming","volume":"23","author":"Sato","year":"2022","journal-title":"EMBO Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1126\/science.adt0743","article-title":"Rhythmic liver drives feeding behavior","volume":"386","author":"Ray","year":"2024","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Perez-Diaz-Del-Campo, N., Castelnuovo, G., Caviglia, G.P., Armandi, A., Rosso, C., and Bugianesi, E. (2022). Role of Circadian Clock on the Pathogenesis and Lifestyle Management in Non-Alcoholic Fatty Liver Disease. Nutrients, 14.","DOI":"10.3390\/nu14235053"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Liu, M., Zhang, Z., Chen, Y., Feng, T., Zhou, Q., and Tian, X. (2023). Circadian clock and lipid metabolism disorders: A potential therapeutic strategy for cancer. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1292011"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Luo, Y., Meng, X., Cui, L., and Wang, S. (2024). Circadian Regulation of Lipid Metabolism during Pregnancy. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252111491"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"Jc16","DOI":"10.7326\/J23-0117","article-title":"In T2DM with obesity, time-restricted eating increased weight loss and reduced HbA(1c) level at 6 mo","volume":"177","author":"Pappachan","year":"2024","journal-title":"Ann. Intern. Med."},{"key":"ref_12","first-page":"1946","article-title":"Time-Restricted Eating Tested for Weight Loss in Type 2 Diabetes","volume":"330","author":"Harris","year":"2023","journal-title":"JAMA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e14027","DOI":"10.1111\/apha.14027","article-title":"Time-restricted eating for chronodisruption-related chronic diseases","volume":"239","author":"Cheng","year":"2023","journal-title":"Acta Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/s41467-022-28662-5","article-title":"Randomized controlled trial for time-restricted eating in healthy volunteers without obesity","volume":"13","author":"Xie","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.cmet.2019.11.004","article-title":"Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome","volume":"31","author":"Wilkinson","year":"2020","journal-title":"Cell Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1016\/j.cmet.2018.04.010","article-title":"Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes","volume":"27","author":"Sutton","year":"2018","journal-title":"Cell Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cmet.2017.06.007","article-title":"Mice under Caloric Restriction Self-Impose a Temporal Restriction of Food Intake as Revealed by an Automated Feeder System","volume":"26","author":"Green","year":"2017","journal-title":"Cell Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.cmet.2018.08.011","article-title":"Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories","volume":"29","author":"Mitchell","year":"2019","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109543","DOI":"10.1016\/j.celrep.2021.109543","article-title":"Sex- and age-dependent outcomes of 9-hour time-restricted feeding of a Western high-fat high-sucrose diet in C57BL\/6J mice","volume":"36","author":"Chaix","year":"2021","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.cmet.2014.11.001","article-title":"Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges","volume":"20","author":"Chaix","year":"2014","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1038\/s41467-023-37286-2","article-title":"Time-of-day defines NAD(+) efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice","volume":"14","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1126\/science.aba8984","article-title":"The hepatocyte clock and feeding control chronophysiology of multiple liver cell types","volume":"369","author":"Guan","year":"2020","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41586-021-03934-0","article-title":"Circadian autophagy drives iTRF-mediated longevity","volume":"598","author":"Ulgherait","year":"2021","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cmet.2018.08.004","article-title":"Time-Restricted Feeding Prevents Obesity and Metabolic Syndrome in Mice Lacking a Circadian Clock","volume":"29","author":"Chaix","year":"2019","journal-title":"Cell Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1126\/science.abl8007","article-title":"Time-restricted feeding mitigates obesity through adipocyte thermogenesis","volume":"378","author":"Hepler","year":"2022","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/s42255-021-00395-7","article-title":"The liver-clock coordinates rhythmicity of peripheral tissues in response to feeding","volume":"3","author":"Manella","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.cmet.2024.01.009","article-title":"Interorgan rhythmicity as a feature of healthful metabolism","volume":"36","author":"Bass","year":"2024","journal-title":"Cell Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e2417678121","DOI":"10.1073\/pnas.2417678121","article-title":"Genetic synchronization of the brain and liver molecular clocks defend against chrono-metabolic disease","volume":"121","author":"Woodie","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eabo2896","DOI":"10.1126\/sciadv.abo2896","article-title":"The central clock suffices to drive the majority of circulatory metabolic rhythms","volume":"8","author":"Petrus","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"jci170998","DOI":"10.1172\/JCI170998","article-title":"Circadian disruption, clock genes, and metabolic health","volume":"134","author":"Schrader","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1016\/j.jgg.2025.04.014","article-title":"The circadian clock at the intersection of metabolism and aging\u2014Emerging roles of metabolites","volume":"52","author":"Dong","year":"2025","journal-title":"J. Genet. Genom."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"21453","DOI":"10.1073\/pnas.0909591106","article-title":"Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression","volume":"106","author":"Vollmers","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.cmet.2022.12.006","article-title":"Diurnal transcriptome landscape of a multi-tissue response to time-restricted feeding in mammals","volume":"35","author":"Deota","year":"2023","journal-title":"Cell Metab."},{"key":"ref_34","first-page":"54052","article-title":"The Treadmill Fatigue Test: A Simple, High-throughput Assay of Fatigue-like Behavior for the Mouse","volume":"11","author":"Dougherty","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Liu, S., Zhuo, K., Wang, Y., Wang, X., and Zhao, Y. (2024). Prolonged Sleep Deprivation Induces a Reprogramming of Circadian Rhythmicity with the Hepatic Metabolic Transcriptomic Profile. Biology, 13.","DOI":"10.3390\/biology13070532"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"gix120","DOI":"10.1093\/gigascience\/gix120","article-title":"SOAPnuke: A MapReduce acceleration-supported software for integrated quality control and preprocessing of high-throughput sequencing data","volume":"7","author":"Chen","year":"2018","journal-title":"Gigascience"},{"key":"ref_37","unstructured":"The R Team (2014). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkz114","article-title":"The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1177\/0748730410379711","article-title":"JTK_CYCLE: An efficient nonparametric algorithm for detecting rhythmic components in genome-scale data sets","volume":"25","author":"Hughes","year":"2010","journal-title":"J. Biol. Rhythm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1093\/bioinformatics\/btz730","article-title":"CircaCompare: A method to estimate and statistically support differences in mesor, amplitude and phase, between circadian rhythms","volume":"36","author":"Parsons","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_42","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.cmet.2012.04.019","article-title":"Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet","volume":"15","author":"Hatori","year":"2012","journal-title":"Cell Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1055\/a-1792-4240","article-title":"Circadian Regulation of Gene Expression and Metabolism in the Liver","volume":"42","author":"Guan","year":"2022","journal-title":"Semin. Liver. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e162515","DOI":"10.1172\/JCI162515","article-title":"Gut microbes and the liver circadian clock partition glucose and lipid metabolism","volume":"133","author":"Frazier","year":"2023","journal-title":"J. Clin. Invest."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"122814","DOI":"10.1016\/j.lfs.2024.122814","article-title":"Regulation of metabolism by circadian rhythms: Support from time-restricted eating, intestinal microbiota & omics analysis","volume":"351","author":"Xie","year":"2024","journal-title":"Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1038\/s44318-024-00121-5","article-title":"Circadian regulation of macromolecular complex turnover and proteome renewal","volume":"43","author":"Seinkmane","year":"2024","journal-title":"EMBO J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2221450","DOI":"10.1080\/19490976.2023.2221450","article-title":"Resynchronized rhythmic oscillations of gut microbiota drive time-restricted feeding induced nonalcoholic steatohepatitis alleviation","volume":"15","author":"Xia","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41522-021-00256-x","article-title":"Time-restricted feeding induces Lactobacillus- and Akkermansia-specific functional changes in the rat fecal microbiota","volume":"7","author":"Palomba","year":"2021","journal-title":"NPJ Biofilms Microbiomes"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1038\/s42003-024-07002-x","article-title":"TRAF7 determines circadian period through ubiquitination and degradation of DBP","volume":"7","author":"Masuda","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"108934","DOI":"10.1016\/j.isci.2024.108934","article-title":"Inter-individual variations in circadian misalignment-induced NAFLD pathophysiology in mice","volume":"27","author":"Koike","year":"2024","journal-title":"iScience"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Verdelho Machado, M. (2024). Circadian Deregulation: Back Facing the Sun Toward Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Development. Nutrients, 16.","DOI":"10.3390\/nu16244294"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"101299","DOI":"10.1016\/j.xcrm.2023.101299","article-title":"Circadian organization of lipid landscape is perturbed in type 2 diabetic patients","volume":"4","author":"Sinturel","year":"2023","journal-title":"Cell Rep. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.tips.2018.07.003","article-title":"Training the Circadian Clock, Clocking the Drugs, and Drugging the Clock to Prevent, Manage, and Treat Chronic Diseases","volume":"39","author":"Sulli","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1038\/s41467-025-56584-5","article-title":"A synthetic chronogenetic gene circuit for programmed circadian drug delivery","volume":"16","author":"Pferdehirt","year":"2025","journal-title":"Nat. Commun."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/193\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:09:12Z","timestamp":1773756552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/2\/193"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":55,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15020193"],"URL":"https:\/\/doi.org\/10.3390\/cells15020193","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]}}}