{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T08:53:48Z","timestamp":1776761628020,"version":"3.51.2"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nature Science Foundation of Sichuan, China","award":["2022NSFSC0106"],"award-info":[{"award-number":["2022NSFSC0106"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Diet-derived advanced glycation end products (dAGEs) are closely associated with obesity and metabolic disorders. This study investigates the therapeutic potential of myriocin (Myr), a sphingolipid synthesis inhibitor, in counteracting dAGE-induced obesity and its underlying mechanisms. Methods: Male C57BL\/6J wild-type mice were randomly assigned to receive either a low-AGE diet or a high-AGE diet with or without the administration of myriocin for a duration of 24 weeks. At the end of the experimental period, blood samples, whole livers, and adipose tissues were harvested for subsequent biochemical, histological, and molecular analyses. Results: Using a 24-week high-AGE diet mouse model, we demonstrate that Myr significantly reduces body weight gain (by 76%) and adipose tissue accumulation, while alleviating hepatic steatosis. Myr improves glucose homeostasis by lowering fasting blood glucose (a 44.5% reduction), enhancing oral glucose tolerance, and restoring hepatic glycolysis\/gluconeogenesis balance via upregulating glucokinase and suppressing G6pc. Notably, Myr reduces serum LDL-C, TG, and TC levels by 52.3%, 51.8%, and 48.8%, respectively, and ameliorates liver dysfunction as evidenced by normalized ALT\/AST activities. Metabolomics reveal Myr reshapes amino acid, carbohydrate, and lipid metabolism pathways. Mechanistically, Myr suppresses lipogenesis by downregulating Srebp1, Fasn, and Acc, while activating AMPK-PGC1\u03b1 signaling to enhance mitochondrial biogenesis (a 2.1-fold increase in mtDNA) and thermogenesis via Ucp1 upregulation in brown and white adipose tissues. Conclusions: Our findings unveil Myr as a novel dual regulator of lipid and glucose metabolism through AMPK-PGC1\u03b1-mediated mitochondrial activation, providing the first evidence of sphingolipid inhibition as a therapeutic strategy against dAGE-induced metabolic syndrome. This study establishes a multifaceted mechanism involving hepatic lipid regulation, adipose browning, and systemic metabolic reprogramming, advancing potential clinical applications for obesity-related disorders.<\/jats:p>","DOI":"10.3390\/nu17091549","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T05:10:32Z","timestamp":1746076232000},"page":"1549","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Myriocin Restores Metabolic Homeostasis in dAGE-Exposed Mice via AMPK-PGC1\u03b1-Mediated Mitochondrial Activation and Systemic Lipid\/Glucose Regulation"],"prefix":"10.3390","volume":"17","author":[{"given":"Libo","family":"He","sequence":"first","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"},{"name":"College of Food and Biological Engineering, Chengdu University, Chengdu 610106, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5039-2845","authenticated-orcid":false,"given":"Jinye","family":"Dang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hairui","family":"Xue","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaxiu","family":"Cai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guohua","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhui","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Binghua","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, College of Medicine, Chengdu University, Chengdu 610106, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yali","family":"Dai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yating","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiran","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Chengdu Medical College, Chengdu 610500, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9091-7100","authenticated-orcid":false,"given":"Jinlin","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"},{"name":"College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4683-9325","authenticated-orcid":false,"given":"Ke","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China"},{"name":"Microbiology and Metabolic Engineering Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.jada.2004.05.214","article-title":"Advanced glycoxidation end products in commonly consumed foods","volume":"104","author":"Goldberg","year":"2004","journal-title":"J. Am. Diet. Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.2337\/diabetes.54.8.2314","article-title":"Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake","volume":"54","author":"Sandu","year":"2005","journal-title":"Diabetes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"170","DOI":"10.3109\/09637486.2015.1137889","article-title":"Dietary consumption of advanced glycation end products and risk of metabolic syndrome","volume":"67","author":"Angoorani","year":"2016","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Baye, E., de Courten, M.P.J., Walker, K., Ranasinha, S., Earnest, A., Forbes, J.M., and de Courten, B. (2017). Effect of dietary advanced glycation end products on inflammation and cardiovascular risks in healthy overweight adults: A randomised crossover trial. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-04214-6"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1016\/j.jacl.2016.07.001","article-title":"Low advanced glycation end product diet improves the lipid and inflammatory profiles of prediabetic subjects","volume":"10","author":"Currenti","year":"2016","journal-title":"J. Clin. Lipidol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1161\/CIRCRESAHA.121.318093","article-title":"Obesity, Adipose Tissue and Vascular Dysfunction","volume":"128","author":"Koenen","year":"2021","journal-title":"Circ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2018.11.002","article-title":"New Advances in Adaptive Thermogenesis: UCP1 and Beyond","volume":"29","author":"Chouchani","year":"2019","journal-title":"Cell Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/oby.20605","article-title":"Evidence for the Role of AMPK in Regulating PGC-1 Alpha Expression and Mitochondrial Proteins in Mouse Epididymal Adipose Tissue","volume":"22","author":"Wan","year":"2014","journal-title":"Obesity"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s12020-018-1826-7","article-title":"Liraglutide induces beige fat development and promotes mitochondrial function in diet induced obesity mice partially through AMPK-SIRT-1-PGC1-alpha cell signaling pathway","volume":"64","author":"Zhou","year":"2019","journal-title":"Endocrine"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ziqubu, K., Mazibuko-Mbeje, S.E., Mthembu, S.X.H., Mabhida, S.E., Jack, B.U., Nyambuya, T.M., Nkambule, B.B., Basson, A.K., Tiano, L., and Dludla, P.V. (2023). Anti-Obesity Effects of Metformin: A Scoping Review Evaluating the Feasibility of Brown Adipose Tissue as a Therapeutic Target. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032227"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E423","DOI":"10.1152\/ajpendo.00133.2016","article-title":"Targeting ceramide metabolism in obesity","volume":"311","author":"Aburasayn","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.2337\/db11-1399","article-title":"Ceramide Mediates Vascular Dysfunction in Diet-Induced Obesity by PP2A-Mediated Dephosphorylation of the eNOS-Akt Complex","volume":"61","author":"Zhang","year":"2012","journal-title":"Diabetes"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.molmet.2017.10.013","article-title":"Inhibition of central de novo ceramide synthesis restores insulin signaling in hypothalamus and enhances \u03b2-cell function of obese Zucker rats","volume":"8","author":"Campana","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1111\/acel.12107","article-title":"Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan","volume":"12","author":"Liu","year":"2013","journal-title":"Aging Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7846","DOI":"10.18632\/aging.202849","article-title":"Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools","volume":"13","author":"Hepowit","year":"2020","journal-title":"Aging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104533","DOI":"10.1016\/j.isci.2022.104533","article-title":"Pharmacological inhibition of sphingolipid synthesis reduces ferroptosis by stimulating the HIF-1 pathway","volume":"25","author":"Liu","year":"2022","journal-title":"iScience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eade6509","DOI":"10.1126\/scitranslmed.ade6509","article-title":"Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging","volume":"15","author":"Lima","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_18","first-page":"974681","article-title":"Modulation of the cellular expression of circulating advanced glycation end-product receptors in type 2 diabetic nephropathy","volume":"2010","author":"Sourris","year":"2010","journal-title":"J. Diabetes Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10565","DOI":"10.1073\/pnas.1913956117","article-title":"Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration","volume":"117","author":"Petit","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cmet.2024.10.016","article-title":"Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis","volume":"37","author":"Gengatharan","year":"2025","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1194\/jlr.M700261-JLR200","article-title":"Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice","volume":"49","author":"Glaros","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1021\/ac8019366","article-title":"Development of a Robust and Repeatable UPLC\u2212MS Method for the Long-Term Metabolomic Study of Human Serum","volume":"81","author":"Zelena","year":"2009","journal-title":"Anal. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/nprot.2012.135","article-title":"Global metabolic profiling of animal and human tissues via UPLC-MS","volume":"8","author":"Want","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.str.2011.02.013","article-title":"Advanced Glycation End Product Recognition by the Receptor for AGEs","volume":"19","author":"Xue","year":"2011","journal-title":"Structure"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ludwig, S. (2021). Diabetes care in the office. Practical Diabetes Care for Healthcare Professionals, Elsevier. [2nd ed.].","DOI":"10.1016\/B978-0-12-820082-7.00003-8"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kobori, T., Ganesh, D., Kumano-Kuramochi, M., Torigoe, K., and Machida, S. (2020). Assay for advanced glycation end products generating intracellular oxidative stress through binding to its receptor. Anal. Biochem., 611.","DOI":"10.1016\/j.ab.2020.114018"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.cmet.2022.03.010","article-title":"SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity","volume":"34","author":"Lee","year":"2022","journal-title":"Cell Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s11010-020-03749-z","article-title":"Mitochondrial bioenergetics, uncoupling protein-2 activity, and reactive oxygen species production in the small intestine of a TNBS-induced colitis rat model","volume":"470","author":"Khachab","year":"2020","journal-title":"Mol. Cell Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.cmet.2016.10.002","article-title":"Adipocyte Ceramides Regulate Subcutaneous Adipose Browning, Inflammation, and Metabolism","volume":"24","author":"Chaurasia","year":"2016","journal-title":"Cell Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/s41586-022-05637-6","article-title":"Insulin-regulated serine and lipid metabolism drive peripheral neuropathy","volume":"614","author":"Handzlik","year":"2023","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cmet.2007.06.001","article-title":"Transcriptional control of brown fat determination by PRDM16","volume":"6","author":"Seale","year":"2007","journal-title":"Cell Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s42255-021-00520-6","article-title":"BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16","volume":"4","author":"Ma","year":"2022","journal-title":"Nat. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1038\/nm.3372","article-title":"Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin","volume":"19","author":"Fullerton","year":"2013","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"E500","DOI":"10.1152\/ajpendo.00361.2005","article-title":"Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue","volume":"290","author":"Watt","year":"2006","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1194\/jlr.M055004","article-title":"CGI-58\/ABHD5 is phosphorylated on Ser239 by protein kinase A: Control of subcellular localization","volume":"56","author":"Schittmayer","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/nrendo.2017.132","article-title":"Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease","volume":"14","author":"Betz","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"E211","DOI":"10.1152\/ajpendo.91014.2008","article-title":"Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome","volume":"297","author":"Yang","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4093\/dmj.2016.40.1.12","article-title":"Brown Fat and Browning for the Treatment of Obesity and Related Metabolic Disorders","volume":"40","author":"Kim","year":"2016","journal-title":"Diabetes Metab. J."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1549\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T08:07:30Z","timestamp":1776758850000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,30]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["nu17091549"],"URL":"https:\/\/doi.org\/10.3390\/nu17091549","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,30]]}}}