Ketogenesis is dispensable for the metabolic adaptations to caloric restriction

Caloric restriction (CR) robustly extends the health and lifespan of diverse species. 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 ketones, we decided to investigate the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2 , the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 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 Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remains robust in mice lacking Hmgcs2 . To gain insight into why deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice began a CR diet. Surprisingly, as CR-fed mice adapt to CR, they no longer engage high levels of ketogenesis during the daily fast. Our work suggests that the benefits of long-term CR in mice are not mediated by ketogenesis.