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When fed once daily, CR\u2010treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketone bodies, we investigated the role of ketogenesis in CR using mice with whole\u2010body ablation of\n                    <jats:italic>Hmgcs2<\/jats:italic>\n                    , the rate\u2010limiting enzyme producing the main ketone body \u03b2\u2010hydroxybutyrate (\u03b2HB). Here, we report that\n                    <jats:italic>Hmgcs2<\/jats:italic>\n                    is largely dispensable for many metabolic benefits of CR, including CR\u2010driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex\u2010specific effects of\n                    <jats:italic>Hmgcs2<\/jats:italic>\n                    on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remained robust in mice lacking\n                    <jats:italic>Hmgcs2<\/jats:italic>\n                    . To gain insight into why the deletion of\n                    <jats:italic>Hmgcs2<\/jats:italic>\n                    does not disrupt CR, we measured fasting \u03b2HB levels as mice initiated a CR diet. Surprisingly, as mice adapt to CR, they no longer engage in high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long\u2010term CR are not mediated by ketogenesis.\n                  <\/jats:p>","DOI":"10.1111\/acel.70318","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T15:54:46Z","timestamp":1765382086000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction"],"prefix":"10.1111","volume":"25","author":[{"given":"Chung\u2010Yang","family":"Yeh","sequence":"first","affiliation":[{"name":"Department of Medicine University of Wisconsin\u2010Madison  Madison Wisconsin USA"},{"name":"William S. 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