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.