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Here, we report hexamethylene bisacetamide (HMBA) as a potent anti\u2010obesity compound. Peripheral and central administration of HMBA to diet\u2010induced obese mice regulated the expression of hypothalamic neuropeptides critical for energy balance, leading to beneficial metabolic effects such as anorexia and weight loss. We found that HMBA bound to MYH9 and ACTG1, which were required for the anti\u2010obesity effects of HMBA in both NPY\u2010expressing and POMC\u2010expressing neurons. The binding of HMBA to MYH9 and ACTG1 elevated the expression of HEXIM1 and enhanced its interaction with MDM2, resulting in the dissociation of the HEXIM1\u2013p53 complex in hypothalamic cells. Subsequently, the free HEXIM1 and p53 translocated to the nucleus, where they downregulated the transcription of orexigenic NPY, but p53 and acetylated histone 3 upregulated that of anorexigenic POMC. Our study points to a previously unappreciated efficacy of HMBA and reveals its mechanism of action in metabolic regulation, which may propose HMBA as a potential therapeutic strategy for obesity.<\/jats:p>","DOI":"10.15252\/emmm.202318024","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T16:57:12Z","timestamp":1700585832000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["HMBA ameliorates obesity by MYH9\u2010 and ACTG1\u2010dependent regulation of hypothalamic neuropeptides"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3932-995X","authenticated-orcid":false,"given":"Seokjae","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5935-088X","authenticated-orcid":false,"given":"Sungjoon","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0461-6622","authenticated-orcid":false,"given":"Nayoun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0631-3660","authenticated-orcid":false,"given":"Eun\u2010Kyoung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,20]]},"reference":[{"key":"BFEMMM202318024_CR1","doi-asserted-by":"crossref","first-page":"W530","DOI":"10.1093\/nar\/gkab294","volume":"49","author":"MF Adasme","year":"2021","unstructured":"Adasme MF, Linnemann KL, Bolz SN, Kaiser F, Salentin S, Haupt VJ, Schroeder M (2021) PLIP 2021: expanding the scope of the protein\u2010ligand interaction profiler to DNA and RNA. 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