{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T14:43:30Z","timestamp":1784126610198,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Health Industry Development Institute (KHIDI)","award":["RS-2025-02219357"],"award-info":[{"award-number":["RS-2025-02219357"]}]},{"name":"Ministry of Health &amp; Welfare, Republic of Korea","award":["RS-2025-02219357"],"award-info":[{"award-number":["RS-2025-02219357"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Insulin resistance is a key driver of metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), progressing to non-alcoholic steatohepatitis (NASH). This study investigated the effects of geniposide (GP) on insulin sensitivity and hepatic fibrosis in a high-fat diet (HFD)-induced NASH model. C57BL\/6 mice were fed an HFD for five weeks and subsequently divided into normal chow (NC), HFD, HFD with GP 50 mg\/kg (GP50), and HFD with GP 100 mg\/kg (GP100) groups. The treatments were administered orally for 12 weeks. GP treatment significantly reduced body weight as well as epididymal fat and liver weights, while no differences were observed in food intake. Improvements in glucose and lipid metabolism were observed in oral glucose tolerance tests, homeostatic model assessment of insulin resistance (HOMA-IR), and blood lipid profiles. Histological analyses revealed that GP suppressed adipocyte hypertrophy and hepatic lipid accumulation and hepatic fibrosis. To further elucidate molecular mechanisms of GP, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was conducted in the liver tissue. GP downregulated expression of inflammatory markers, including F4\/80, tumor necrosis factor (TNF)-\u03b1, and interleukin (IL)-6. GP treatment modulated genes involved in insulin signaling including Janus kinase 2 (JAK2), insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and protein kinase B (AKT1) gene expression levels. This suggests GP suppresses inflammation and mitigates insulin resistance by activating the INSR\u2013IRS2\u2013Akt pathway. Additionally, GP enhanced adenosine monophosphate-activated protein kinase (AMPK) expression, suggesting its potential role in improving glucose and lipid metabolism. In conclusion, GP improves insulin resistance, inflammation, and hepatic fibrosis, highlighting its therapeutic potential for NASH and related metabolic disorders.<\/jats:p>","DOI":"10.3390\/ijms26168079","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T07:41:45Z","timestamp":1755848505000},"page":"8079","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Geniposide Mitigates Insulin Resistance and Hepatic Fibrosis via Insulin Signaling Pathway"],"prefix":"10.3390","volume":"26","author":[{"given":"Seung-Hyun","family":"Oh","sequence":"first","affiliation":[{"name":"Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Seong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2209-6229","authenticated-orcid":false,"given":"Byung-Cheol","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1038\/nature05482","article-title":"Mechanisms linking obesity to insulin resistance and type 2 diabetes","volume":"444","author":"Kahn","year":"2006","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3892\/mi.2024.201","article-title":"Examining the growing challenge: Prevalence of diabetes in young adults (Review)","volume":"5","author":"Murtaza","year":"2025","journal-title":"Med. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/ptr.5775","article-title":"Antiinflammation Effects and Mechanisms Study of Geniposide on Rats with Collagen-Induced Arthritis","volume":"31","author":"Wang","year":"2017","journal-title":"Phytother. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/aps.2008.17","article-title":"Effect of geniposide, a hypoglycemic glucoside, on hepatic regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin","volume":"30","author":"Wu","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Yang, L., Bi, L., Jin, L., Wang, Y., Li, Y., Li, Z., He, W., Cui, H., Miao, J., and Wang, L. (2021). Geniposide Ameliorates Liver Fibrosis Through Reducing Oxidative Stress and Inflammatory Respose, Inhibiting Apoptosis and Modulating Overall Metabolism. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.772635"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1111\/j.2042-7158.2011.01256.x","article-title":"Hepatoprotective effects of geniposide in a rat model of nonalcoholic steatohepatitis","volume":"63","author":"Ma","year":"2011","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7237","DOI":"10.3892\/mmr.2017.7503","article-title":"Geniposide promotes autophagy to inhibit insulin resistance in HepG2 cells via P62\/NF-kappaB\/GLUT-4","volume":"16","author":"Jiang","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1093\/abbs\/gmaa157","article-title":"Geniposide improves insulin resistance through AMPK-mediated Txnip protein degradation in 3T3-L1 adipocytes","volume":"53","author":"Zhao","year":"2021","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153862","DOI":"10.1016\/j.phymed.2021.153862","article-title":"A novel regulatory mechanism of geniposide for improving glucose homeostasis mediated by circulating RBP4","volume":"95","author":"Liu","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"156","DOI":"10.4062\/biomolther.2015.094","article-title":"Comparative Evaluation of Hepatoprotective Activities of Geniposide, Crocins and Crocetin by CCl4-Induced liver Injury in Mice","volume":"24","author":"Chen","year":"2016","journal-title":"Biomol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117061","DOI":"10.1016\/j.jep.2023.117061","article-title":"Bidirectional effects of geniposide in liver injury: Preclinical evidence construction based on meta-analysis","volume":"319","author":"Zeng","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1053\/j.gastro.2007.03.059","article-title":"Obesity, inflammation, and insulin resistance","volume":"132","author":"Shoelson","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1126\/science.271.5249.665","article-title":"IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance","volume":"271","author":"Hotamisligil","year":"1996","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.smim.2014.02.009","article-title":"TNF and MAP kinase signalling pathways","volume":"26","author":"Sabio","year":"2014","journal-title":"Semin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E166","DOI":"10.1152\/ajpendo.00284.2006","article-title":"Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins","volume":"292","author":"Lumeng","year":"2007","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"352371","DOI":"10.1155\/2014\/352371","article-title":"Functional roles of p38 mitogen-activated protein kinase in macrophage-mediated inflammatory responses","volume":"2014","author":"Yang","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.2337\/db08-1261","article-title":"Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle","volume":"58","author":"Hong","year":"2009","journal-title":"Diabetes"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.intimp.2014.04.004","article-title":"Geniposide suppresses LPS-induced nitric oxide, PGE2 and inflammatory cytokine by downregulating NF-kappaB, MAPK and AP-1 signaling pathways in macrophages","volume":"20","author":"Shi","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Boucher, J., Kleinridders, A., and Kahn, C.R. (2014). Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect Biol., 6.","DOI":"10.1101\/cshperspect.a009191"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/s41392-022-01073-0","article-title":"Trends in insulin resistance: Insights into mechanisms and therapeutic strategy","volume":"7","author":"Li","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/414799a","article-title":"Insulin signalling and the regulation of glucose and lipid metabolism","volume":"414","author":"Saltiel","year":"2001","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10277","DOI":"10.1074\/jbc.M111.317453","article-title":"Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance","volume":"287","author":"Shi","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"942","DOI":"10.2337\/diabetes.55.04.06.db05-1265","article-title":"Opposite effect of JAK2 on insulin-dependent activation of mitogen-activated protein kinases and Akt in muscle cells: Possible target to ameliorate insulin resistance","volume":"55","author":"Thirone","year":"2006","journal-title":"Diabetes"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1172\/JCI10762","article-title":"Insulin resistance and cardiovascular disease","volume":"106","author":"Ginsberg","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Handy, R.M., and Holloway, G.P. (2023). Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1151389"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1053\/j.gastro.2008.01.075","article-title":"Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects","volume":"134","author":"Korenblat","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E401","DOI":"10.1152\/ajpendo.00674.2007","article-title":"The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance","volume":"295","author":"Matsuda","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1136\/gutjnl-2015-310798","article-title":"Liver PPARalpha is crucial for whole-body fatty acid homeostasis and is protective against NAFLD","volume":"65","author":"Montagner","year":"2016","journal-title":"Gut"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.cmet.2007.05.002","article-title":"Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states","volume":"5","author":"Badman","year":"2007","journal-title":"Cell Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/s41574-020-0386-0","article-title":"The therapeutic potential of FGF21 in metabolic diseases: From bench to clinic","volume":"16","author":"Geng","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e245","DOI":"10.1038\/emm.2016.81","article-title":"Regulation and function of AMPK in physiology and diseases","volume":"48","author":"Jeon","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.ebiom.2018.01.008","article-title":"AMPK Re-Activation Suppresses Hepatic Steatosis but its Downregulation Does Not Promote Fatty Liver Development","volume":"28","author":"Boudaba","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5097","DOI":"10.1111\/jcmm.15139","article-title":"Geniposide alleviates non-alcohol fatty liver disease via regulating Nrf2\/AMPK\/mTOR signalling pathways","volume":"24","author":"Shen","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"104631","DOI":"10.1016\/j.phrs.2020.104631","article-title":"Geniposide reduces cholesterol accumulation and increases its excretion by regulating the FXR-mediated liver-gut crosstalk of bile acids","volume":"152","author":"Liu","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e21834","DOI":"10.1016\/j.heliyon.2023.e21834","article-title":"Acute and subacute hepatotoxicity of genipin in mice and its potential mechanism","volume":"9","author":"Wang","year":"2023","journal-title":"Heliyon"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1007\/s11154-023-09820-6","article-title":"Towards precision medicine in non-alcoholic fatty liver disease","volume":"24","author":"Francque","year":"2023","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_39","first-page":"198","article-title":"High-fat diet-induced adipose tissue expansion occurs prior to insulin resistance in C57BL\/6J mice","volume":"6","author":"He","year":"2020","journal-title":"Chronic Dis. Transl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8079\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:42Z","timestamp":1760034762000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8079"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":39,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26168079"],"URL":"https:\/\/doi.org\/10.3390\/ijms26168079","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]}}}