{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:17:54Z","timestamp":1785403074381,"version":"3.56.0"},"reference-count":53,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23650487"],"award-info":[{"award-number":["23650487"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K11646"],"award-info":[{"award-number":["19K11646"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"award":["23650487"],"award-info":[{"award-number":["23650487"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]},{"award":["19K11646"],"award-info":[{"award-number":["19K11646"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: To address the limitations of natural curcumin, this study focuses on the functional evaluation of structurally optimized derivatives. We aimed to elucidate structure\u2013activity relationships (SAR) and the stage-specific molecular mechanisms of adipogenesis inhibition using an in vitro cellular assay. Methods: Four novel curcuminoids were synthesized and evaluated in 3T3-L1 preadipocytes against natural curcumin (Curcuminoid I). Efficacy and mechanisms were assessed via cell viability assays, quantitative Oil Red O staining, and time-dependent transcriptional profiling (qPCR\/Western blotting) of the KLF family and master regulators. Results: SAR analysis identified Curcuminoid III (symmetric 3,5-dimethoxy-4-hydroxy) as the most potent and safe candidate, whereas Curcuminoid IV exhibited cytotoxicity. Time-course analysis revealed a distinct step-wise inhibition mechanism wherein Curcuminoid III significantly upregulated the differentiation repressor KLF2 at the immediate-early phase. This rapid modulation effectively prevented the subsequent induction of pro-adipogenic factors, including KLF9, KLF15, PPAR\u03b3, and C\/EBP\u03b1, in the mid-stage (3\u20135 d). Consequently, the expression of the maturation marker aP2 was robustly suppressed by the late stage (5\u20137 d). Conclusions: The symmetric 3,5-dimethoxy-4-hydroxy substitution pattern appears to confer strong anti-adipogenic activity to Curcuminoid III. Early modulation of the KLF2\u2013PPAR\u03b3 axis at the onset of differentiation may initiate a cascading inhibitory effect throughout the adipogenic program. These findings highlight the potential of structurally optimized plant-derived bioactive compounds as regulators of metabolic cell fate.<\/jats:p>","DOI":"10.3390\/nu18081285","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T07:15:08Z","timestamp":1776669308000},"page":"1285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2013Activity Relationship and Stage-Dependent Inhibition of Adipogenesis by Curcuminoid Derivatives in 3T3-L1 Cells"],"prefix":"10.3390","volume":"18","author":[{"given":"Suzuna","family":"Araki","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Ueda","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hinako","family":"Ayabe","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rio","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Kohama","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouta","family":"Maenishi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7730-8538","authenticated-orcid":false,"given":"Changsun","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Kwon","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6691-9464","authenticated-orcid":false,"given":"Toshiya","family":"Masuda","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7194-3053","authenticated-orcid":false,"given":"Miwako","family":"Deguchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Saeki","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3194-7937","authenticated-orcid":false,"given":"DongHo","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition and Metabolic Regulation, Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, 2-1-132 Morinomiya, Joto-ku, Osaka 536-8525, 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