{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:59:22Z","timestamp":1790891962582,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T00:00:00Z","timestamp":1676073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Obesity is a complex multifactorial disease characterized by excessive adiposity, and is linked to an increased risk of nonalcoholic fatty liver disease (NAFLD). Flavonoids are natural polyphenolic compounds that exert interesting pharmacological effects as antioxidant, anti-inflammatory, and lipid-lowering agents. In the present study, we investigated the possible therapeutic effects of the flavonoid chrysin on obesity and NAFLD in rats, and the role of AMP-activated protein kinase (AMPK)\/mammalian target of rapamycin (mTOR) pathways in mediating these effects. Method: Thirty-two Wistar male rats were divided into two groups: the control group and the obese group. Obesity was induced by feeding with an obesogenic diet for 3 months. The obese rats were subdivided into four subgroups, comprising an untreated group, and three groups treated orally with different doses of chrysin (25, 50, and 75 mg\/kg\/day for one month). Results revealed that chrysin treatment markedly ameliorated the histological changes and significantly and dose-dependently reduced the weight gain, hyperglycemia, and insulin resistance in the obese rats. Chrysin, besides its antioxidant boosting effects (increased GSH and decreased malondialdehyde), activated the AMPK pathway and suppressed the mTOR and lipogenic pathways, and stimulated expression of the genes controlling mitochondrial biogenesis in the hepatic tissues in a dose-dependent manner. In conclusion, chrysin could be a promising candidate for the treatment of obesity and associated NAFLD, aiding in attenuating weight gain and ameliorating glucose and lipid homeostasis and adipokines, boosting the hepatic mitochondrial biogenesis, and modulating AMPK\/mTOR\/SREBP-1c signaling pathways.<\/jats:p>","DOI":"10.3390\/molecules28041734","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T02:14:11Z","timestamp":1676254451000},"page":"1734","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["The Anti-Obesity and Anti-Steatotic Effects of Chrysin in a Rat Model of Obesity Mediated through Modulating the Hepatic AMPK\/mTOR\/lipogenesis Pathways"],"prefix":"10.3390","volume":"28","author":[{"given":"Ghaleb","family":"Oriquat","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0982-7106","authenticated-orcid":false,"given":"Inas M.","family":"Masoud","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria 21311, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6791-9850","authenticated-orcid":false,"given":"Maher A.","family":"Kamel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hebatallah Mohammed","family":"Aboudeya","sequence":"additional","affiliation":[{"name":"Department of Human Physiology, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa B.","family":"Bakir","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7251-8648","authenticated-orcid":false,"given":"Sara A.","family":"Shaker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Woolsey, S.J., Gong, I., Kim, R., Levstik, M., Beaton, M., and Tirona, R. (2013). Regulation of Cytochrome P450 3A4 in Non-Alcoholic Fatty Liver Disease by Fibroblast Growth Factor 21, Wiley Online Library.","DOI":"10.1096\/fasebj.27.1_supplement.lb537"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4236\/jbise.2021.142004","article-title":"Impact of Obesity in Non-Alcoholic Fatty Liver Disease","volume":"14","author":"Uthayakumar","year":"2021","journal-title":"J. Biomed. Sci. Eng."},{"key":"ref_3","first-page":"5091","article-title":"The therapeutic effects of bee venom on some metabolic and antioxidant parameters associated with HFD-induced non-alcoholic fatty liver in rats","volume":"15","author":"Hanafi","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.metabol.2018.11.014","article-title":"Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics","volume":"92","author":"Polyzos","year":"2019","journal-title":"Metabolism"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.metabol.2015.11.006","article-title":"Adipokines in nonalcoholic fatty liver disease","volume":"65","author":"Polyzos","year":"2016","journal-title":"Metabolism"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3803\/EnM.2018.33.1.33","article-title":"Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease","volume":"33","author":"Boutari","year":"2018","journal-title":"Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"R235","DOI":"10.1530\/EJE-16-0927","article-title":"EJE PRIZE 2017: Hypothalamic AMPK: A golden target against obesity?","volume":"176","year":"2017","journal-title":"Eur. J. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/s41392-022-01149-x","article-title":"Signaling pathways in obesity: Mechanisms and therapeutic interventions","volume":"7","author":"Wen","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.cmet.2011.03.009","article-title":"AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-Induced Insulin-Resistant Mice","volume":"13","author":"Li","year":"2011","journal-title":"Cell Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.bbrc.2010.11.127","article-title":"Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans","volume":"404","author":"Gauthier","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1194\/jlr.P022905","article-title":"Insulin sensitive and resistant obesity in humans: AMPK activity, oxidative stress, and depot-specific changes in gene expression in adipose tissue","volume":"53","author":"Xu","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7219","DOI":"10.1073\/pnas.1600581113","article-title":"Disruption of the AMPK\u2013TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion","volume":"113","author":"Chen","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s13238-017-0409-3","article-title":"mTORC1 signaling in hepatic lipid metabolism","volume":"9","author":"Han","year":"2018","journal-title":"Protein Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"101922","DOI":"10.1016\/j.clinre.2022.101922","article-title":"The mTORC1\/AMPK pathway plays a role in the beneficial effects of semaglutide (GLP-1 receptor agonist) on the liver of obese mice","volume":"46","author":"Aguila","year":"2022","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3389\/fchem.2020.00407","article-title":"Rapamycin-loaded mPEG-PLGA nanoparticles ameliorate hepatic steatosis and liver injury in non-alcoholic fatty liver disease","volume":"8","author":"Zhao","year":"2020","journal-title":"Front. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1097\/MED.0b013e32833c3026","article-title":"Mitochondrial dysfunction in obesity","volume":"17","author":"Bournat","year":"2010","journal-title":"Curr. Opin. Endocrinol. Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41387-020-00130-3","article-title":"Neohesperidin enhances PGC-1\u03b1-mediated mitochondrial biogenesis and alleviates hepatic steatosis in high fat diet fed mice","volume":"10","author":"Wang","year":"2020","journal-title":"Nutr. Diabetes"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/S0140-6736(21)01919-X","article-title":"Obesity management as a primary treatment goal for type 2 diabetes: Time to reframe the conversation","volume":"399","author":"Lingvay","year":"2021","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s00535-017-1415-1","article-title":"Current and future pharmacological therapies for NAFLD\/NASH","volume":"53","author":"Sumida","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1007\/s00210-019-01705-3","article-title":"Chrysin ameliorates nonalcoholic fatty liver disease in rats","volume":"392","author":"Pai","year":"2019","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.jtcme.2019.09.002","article-title":"Chrysin mitigated obesity by regulating energy intake and expenditure in rats","volume":"10","author":"Pai","year":"2020","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"440","DOI":"10.9734\/IJBCRR\/2014\/10649","article-title":"Maternal Obesity and Malnutrition in Rats Differentially Affect Glucose Sensing in the Muscles and Adipose Tissues in the Offspring","volume":"4","author":"Kamel","year":"2014","journal-title":"Int. J. Biochem. Res. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.2337\/dc06-0070","article-title":"New Insights on the Simultaneous Assessment of Insulin Sensitivity and \u03b2-Cell Function With the HOMA2 Method","volume":"29","author":"Caumo","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the Folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/0003-2697(80)90139-6","article-title":"Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine","volume":"106","author":"Griffith","year":"1980","journal-title":"Anal. Biochem."},{"key":"ref_26","unstructured":"Draper, H., and Hadley, M. (1990). Methods in Enzymology, Elsevier."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/978-1-0716-0704-6_11","article-title":"Enzymatic Quantification of Liver Lipids After Folch Extraction","volume":"2164","author":"Minniti","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.cca.2020.01.015","article-title":"The exchangeable apolipoproteins in lipid metabolism and obesity","volume":"503","author":"Su","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1111\/j.1439-0396.2007.00752.x","article-title":"Liver lipid metabolism","volume":"92","author":"Nguyen","year":"2008","journal-title":"J. Anim. Physiol. Anim. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14784","DOI":"10.1038\/s41598-019-51377-5","article-title":"Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice","volume":"9","author":"Parsanathan","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Salman, M., Kamel, M.A., El-Nabi, S.E.H., Ismail, A.H.A., Ullah, S., Al-Ghamdi, A., Hathout, H.M.R., and El-Garawani, I.M. (2022). The regulation of HBP1, SIRT1, and SREBP-1c genes and the related microRNAs in non-alcoholic fatty liver rats: The association with the folic acid anti-steatosis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0265455"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ejphar.2019.01.039","article-title":"Evaluating the therapeutic potential of one-carbon donors in nonalcoholic fatty liver disease","volume":"847","author":"Bakir","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"758317","DOI":"10.3389\/fcell.2021.758317","article-title":"Possible Involvement of the Nutrient and Energy Sensors mTORC1 and AMPK in Cell Fate Diversification in a Non-Metazoan Organism","volume":"9","author":"Gross","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1101\/gad.339895.120","article-title":"AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation","volume":"34","author":"Hellberg","year":"2020","journal-title":"Genes Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.cmet.2013.08.002","article-title":"A Central Role for mTOR in Lipid Homeostasis","volume":"18","author":"Lamming","year":"2013","journal-title":"Cell Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"152532","DOI":"10.1016\/j.tox.2020.152532","article-title":"Resveratrol ameliorates disorders of mitochondrial biogenesis and mitophagy in rats continuously exposed to benzo(a)pyrene from embryonic development through adolescence","volume":"442","author":"Chen","year":"2020","journal-title":"Toxicology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1800795","DOI":"10.1002\/mnfr.201800795","article-title":"Sulforaphane improves lipid metabolism by enhancing mitochondrial function and biogenesis in vivo and in vitro","volume":"63","author":"Lei","year":"2019","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8713","DOI":"10.3390\/ijms15058713","article-title":"Role of Mitochondria in Nonalcoholic Fatty Liver Disease","volume":"15","author":"Nassir","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Stompor-Gor\u0105cy, M., Bajek-Bil, A., and Machaczka, M. (2021). Chrysin: Perspectives on Contemporary Status and Future Possibilities as Pro-Health Agent. Nutrients, 13.","DOI":"10.3390\/nu13062038"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"111906","DOI":"10.1016\/j.biopha.2021.111906","article-title":"An updated review on the versatile role of chrysin in neurological diseases: Chemistry, pharmacology, and drug delivery approaches","volume":"141","author":"Talebi","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.biopha.2017.06.003","article-title":"An overview on immunoregulatory and anti-inflammatory properties of chrysin and flavonoids substances","volume":"92","author":"Zeinali","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"114320","DOI":"10.1016\/j.jep.2021.114320","article-title":"Danning tablets alleviate high fat diet-induced obesity and fatty liver in mice via modulating SREBP pathway","volume":"279","author":"Ma","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1111\/j.1745-7254.2008.00807.x","article-title":"Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase","volume":"29","author":"Shang","year":"2008","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1016\/j.bcp.2013.02.007","article-title":"Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK\u2013mTOR\u2013SREBP signaling pathway","volume":"85","author":"Quan","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_45","first-page":"701","article-title":"LRG ameliorates steatohepatitis by activating the AMPK\/mTOR\/SREBP1 signaling pathway in C57BL\/6J mice fed a high-fat diet","volume":"20","author":"Hao","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"173244","DOI":"10.1016\/j.ejphar.2020.173244","article-title":"Berbamine induced AMPK activation regulates mTOR\/SREBP-1c axis and Nrf2\/ARE pathway to allay lipid accumulation and oxidative stress in steatotic HepG2 cells","volume":"882","author":"Sharma","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.toxrep.2014.02.003","article-title":"Hypolipidemic action of chrysin on Triton WR-1339-induced hyperlipidemia in female C57BL\/6 mice","volume":"1","author":"Zarzecki","year":"2014","journal-title":"Toxicol. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kicinska, A., and Jarmuszkiewicz, W. (2020). Flavonoids and Mitochondria: Activation of Cytoprotective Pathways?. Molecules, 25.","DOI":"10.3390\/molecules25133060"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/hep.27134","article-title":"Is the adiponectin-AMPK-mitochondrial axis involved in progression of nonalcoholic fatty liver disease?","volume":"60","author":"Dasarathy","year":"2014","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12017","DOI":"10.1073\/pnas.0705070104","article-title":"AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha","volume":"104","author":"Handschin","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/nature07813","article-title":"AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity","volume":"458","author":"Feige","year":"2009","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.cmet.2008.07.007","article-title":"SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth","volume":"8","author":"Porstmann","year":"2008","journal-title":"Cell Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7510","DOI":"10.18632\/aging.102263","article-title":"MiR-27a promotes insulin resistance and mediates glucose metabolism by targeting PPAR-\u03b3-mediated PI3K\/AKT signaling","volume":"11","author":"Chen","year":"2019","journal-title":"Aging"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1139\/cjpp-2014-0412","article-title":"Chrysin treatment improves diabetes and its complications in liver, brain, and pancreas in streptozotocin-induced diabetic rats","volume":"94","author":"Samarghandian","year":"2015","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e21960","DOI":"10.1002\/jbt.21960","article-title":"Restorative effects of Chrysin pretreatment on oxidant\u2013antioxidant status, inflammatory cytokine production, and apoptotic and autophagic markers in acute paracetamol-induced hepatotoxicity in rats: An experimental and biochemical study","volume":"31","author":"Eldutar","year":"2017","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"17787","DOI":"10.1073\/pnas.0902380106","article-title":"Insulin resistance is a cellular antioxidant defense mechanism","volume":"106","author":"Hoehn","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/4\/1734\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:31:42Z","timestamp":1760121102000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/4\/1734"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,11]]},"references-count":56,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["molecules28041734"],"URL":"https:\/\/doi.org\/10.3390\/molecules28041734","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,11]]}}}