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When fed once daily, CR-treated 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-body ablation of\n                  <jats:italic>Hmgcs2<\/jats:italic>\n                  , the rate-limiting enzyme producing the main ketone body \u03b2-hydroxybutyrate (\u03b2HB). Here, we report that\n                  <jats:italic>Hmgcs2<\/jats:italic>\n                  is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific 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 high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long-term CR are not mediated by ketogenesis.\n                <\/jats:p>","DOI":"10.1101\/2025.05.29.656153","type":"posted-content","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T07:45:12Z","timestamp":1748763912000},"source":"Crossref","is-referenced-by-count":0,"title":["Ketogenesis is dispensable for the metabolic adaptations to caloric restriction"],"prefix":"10.64898","author":[{"given":"Chung-Yang","family":"Yeh","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis L.","family":"Borgelt","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brynn J.","family":"Vogt","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa A.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ted T.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Grunow","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Sonsalla","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"},{"name":"Comparative Biomedical Sciences Graduate Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reji","family":"Babygirija","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"},{"name":"Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"},{"name":"Endocrinology and Reproductive Physiology Graduate Program, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela E.","family":"Trautman","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariah F.","family":"Calubag","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. 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