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Over the years, the field has come to appreciate that ketones are much more than just a fuel source supporting neuronal metabolism, as many other oxidative organs, such as the heart and skeletal muscle, are capable of metabolizing ketones. Furthermore, ketones appear to be an important fuel source for exercising muscle. Beyond supporting ATP production, it is also becoming widely recognized that ketones are powerful signalling molecules, as they serve as ligands for G\u2010protein coupled receptors and can even modify gene expression via regulating DNA post\u2010translational modifications. As they play a key role in supporting whole\u2010body physiology, it is not surprising that perturbations in ketone metabolism can contribute to various pathologies, particularly in relation to cardiometabolic diseases. Some of the strongest evidence supporting the aforementioned statement is seen for both heart failure and type 2 diabetes. Accordingly, we will review herein the multifaceted roles of ketones in supporting whole\u2010body physiology, while interrogating the evidence to suggest whether modifying ketone metabolism may have a therapeutic role in the management of heart failure and type 2 diabetes.<\/jats:p>","DOI":"10.1113\/ep092243","type":"journal-article","created":{"date-parts":[[2025,5,11]],"date-time":"2025-05-11T11:32:22Z","timestamp":1746963142000},"page":"1-13","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The multifaceted roles of ketones in physiology"],"prefix":"10.1113","volume":"111","author":[{"given":"Seyed Amirhossein","family":"Tabatabaei Dakhili","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunyan","family":"Yang","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus J.","family":"Stenlund","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9574-5707","authenticated-orcid":false,"given":"John R.","family":"Ussher","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2022.109129"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.03.017"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm1005012"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.017355"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1152\/jappl.1978.44.1.5","article-title":"Changes induced by exercise in rates of turnover and oxidation of ketone bodies in fasting man","volume":"44","author":"Balasse E. 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