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In response to stress or fasting, glucocorticoid (GC) levels are elevated to promote food intake. This involves GC-induced expression of the orexigenic neuropeptides in agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) via the GC receptor (GR). Here, we report a selective GR modulator (SGRM) that suppresses GR-induced transcription of genes with non-classical glucocorticoid response elements (GREs) such as <jats:italic>Agrp<\/jats:italic>-GRE, but not with classical GREs, and via this way may serve as a novel anti-obesity agent. We have identified a novel SGRM, 2<jats:italic>-O-trans<\/jats:italic>-<jats:italic>p<\/jats:italic>-coumaroylalphitolic acid (Zj7), a triterpenoid extracted from the <jats:italic>Ziziphus jujube<\/jats:italic> plant, that selectively suppresses GR transcriptional activity in <jats:italic>Agrp<\/jats:italic>-GRE without affecting classical GREs. Zj7 reduces the expression of orexigenic genes in the ARC and exerts a significant anorexigenic effect with weight loss in both high fat diet-induced obese and genetically obese <jats:italic>db\/db<\/jats:italic> mouse models. Transcriptome analysis showed that Zj7 represses the expression of a group of orexigenic genes including <jats:italic>Agrp<\/jats:italic> and <jats:italic>Npy<\/jats:italic> induced by the synthetic GR ligand dexamethasone (Dex) in the hypothalamus. Taken together, Zj7, as a selective GR modulator, showed beneficial metabolic activities, in part by suppressing GR activity in non-classical GREs in orexigenic genes. This study demonstrates that a potential anorexigenic molecule may allow GRE-specific inhibition of GR transcriptional activity, which is a promising approach for the treatment of metabolic disorders.<\/jats:p>","DOI":"10.1038\/s41598-024-58546-1","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T10:01:38Z","timestamp":1712138498000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Characterization of a new selective glucocorticoid receptor modulator with anorexigenic activity"],"prefix":"10.1038","volume":"14","author":[{"given":"Junekyoung","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeonghun","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young A.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Intae","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jooseon","family":"Cha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Won","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoonae","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong-Su","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seunghee","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,3]]},"reference":[{"key":"58546_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1385\/endo:14:1:001","volume":"14","author":"MT Bluet-Pajot","year":"2001","unstructured":"Bluet-Pajot, M. 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