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We investigate whether the elevation of plasma levels of the ketone body \u03b2\u2010hydroxybutyrate, achieved through the in\u00a0vivo administration of its precursor 1,3\u2010butanediol (BD) to rats, could impact interscapular BAT (iBAT) mitochondrial biochemistry and functionality. We examined the effects induced by BD within 3\u2009h and after 2\u2009weeks of treatment. A large\u2010scale quantitative proteomics approach, coupling liquid chromatography with tandem mass spectrometry (LC\u2013MS\/MS) analysis, and Western blot associated with functional studies by respirometry allowed us to evaluate the changes in iBAT mitochondrial protein expression and bioenergetics induced by BD. BD administration increased \u03b2\u2010hydroxybutyrate plasma levels, which correlated with an enhancement in iBAT mitochondrial respiration rate, likely due to the activation of the respiratory chain and uncoupling protein\u20101. The proteomic analysis demonstrated that BD influenced the mitochondrial levels of specific subunits belonging to the five respiratory complexes, uncoupling protein\u20101, and proteins involved in propanoate metabolism. BD administration also induced lysine \u03b2\u2010hydroxybutyrylation of mitochondrial proteins, including specific subunits of the respiratory chain complexes and uncoupling protein\u20101. Most of the BD\u2010induced effects were observed within 3\u2009h of its administration and persisted\/increased after 2\u2009weeks of treatment. In conclusion, by using BD to increase \u03b2\u2010hydroxybutyrate levels, we provide evidence supporting the role of \u03b2\u2010hydroxybutyrate as a signaling molecule capable of rapidly modulating BAT physiology by acting at the mitochondrial level.<\/jats:p>","DOI":"10.1096\/fj.202401592rr","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T10:10:44Z","timestamp":1732270244000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rapid modulation of interscapular brown adipose tissue mitochondrial activity by ketosis induced by 1,3\u2010butanediol administration to rats"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0522-1788","authenticated-orcid":false,"given":"Paola","family":"Venditti","sequence":"first","affiliation":[{"name":"Department of Biology University of Naples Federico II, Complesso Monte Sant'Angelo  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9169-3452","authenticated-orcid":false,"given":"Gabriella","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences University of Naples Federico II, Complesso Monte Sant'Angelo  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8820-4694","authenticated-orcid":false,"given":"Vincenzo","family":"Migliaccio","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biology \u201cA. 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