{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:44:09Z","timestamp":1790084649815,"version":"4.0.1"},"reference-count":48,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bisa Research Grant of Keimyung University","award":["20230361"],"award-info":[{"award-number":["20230361"]}]},{"award":["20230361"],"award-info":[{"award-number":["20230361"]}],"id":[{"id":"https:\/\/ror.org\/00tjv0s33","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obesity is a major metabolic disorder characterized by excessive lipid accumulation and adipocyte differentiation. The mitogen-activated protein kinase kinase 5 (MEK5) signaling pathway has been implicated in diverse cellular processes; however, its role in adipogenesis remains incompletely understood. In this study, we investigated the anti-adipogenic effects of BIX02189, a selective MEK5 inhibitor, using 3T3-L1 adipocytes, human adipose-derived stem cells (hASCs), and zebrafish models. Treatment with BIX02189 significantly reduced lipid accumulation and triglyceride content during adipocyte differentiation in a dose-dependent manner without marked cytotoxicity. BIX02189 effectively suppressed MEK5 phosphorylation and downregulated the expression of key adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPAR-\u03b3) and CCAAT\/enhancer-binding protein alpha (C\/EBP-\u03b1). In addition, BIX02189 decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and STAT5, as well as the expression of lipogenic markers such as fatty acid synthase (FAS), perilipin A, and leptin. Conversely, BIX02189 enhanced AMP-activated protein kinase (AMPK) phosphorylation and markedly reduced the protein and mRNA expression of acetyl-CoA carboxylase (ACC), a key enzyme involved in fatty acid synthesis. Similar anti-adipogenic effects were observed in hASCs. Furthermore, BIX02189 significantly attenuated lipid accumulation in a zebrafish obesity model without affecting body length or causing overt toxicity. Collectively, these findings demonstrate that pharmacological inhibition of MEK5 suppresses adipogenesis and lipid accumulation through regulation of the STAT3\/STAT5\u2013PPAR-\u03b3 axis and activation of AMPK signaling. These findings provide the first evidence that MEK5 inhibition exerts anti-adipogenic effects in adipocytes and zebrafish, highlighting the MEK5 signaling pathway as a previously unrecognized regulator of adipogenesis and lipid metabolism.<\/jats:p>","DOI":"10.3390\/ijms27146468","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T10:35:52Z","timestamp":1784630152000},"page":"6468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["BIX02189 Suppresses Adipogenesis and Lipid Accumulation Through Inhibition of MEK5-STAT3\/STAT5 Signaling and Activation of AMPK in Adipocytes and Zebrafish"],"prefix":"10.3390","volume":"27","author":[{"given":"Nivethasri Lakshmana","family":"Perumal","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muneer","family":"Hussain","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4653-1048","authenticated-orcid":false,"given":"Dae-Gu","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, College of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Stephens","sequence":"additional","affiliation":[{"name":"Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0056-1556","authenticated-orcid":false,"given":"Gi-Young","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Daegu Catholic University School of Medicine, Nam-Gu, Daegu 42472, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byeong-Churl","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, College of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-gu, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/35007508","article-title":"Obesity as a medical problem","volume":"404","author":"Kopelman","year":"2000","journal-title":"Nature"},{"key":"ref_2","unstructured":"NCD Risk Factor Collaboration (NCD-RisC) (2024). 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