Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction

Area of Science:

• Metabolic research
• Aging and longevity studies
• Biochemistry

Background:

• Caloric restriction (CR) is known to extend lifespan and healthspan across species.
• CR involves daily fasting periods, which typically increase ketone body levels.
• Ketone bodies, like β-hydroxybutyrate (βHB), are produced via ketogenesis, a process regulated by Hmgcs2.

Purpose of the Study:

• To investigate the role of ketogenesis, specifically βHB production, in mediating the metabolic benefits of CR.
• To determine if Hmgcs2, the rate-limiting enzyme in ketogenesis, is required for CR's effects on health and lifespan.

Main Methods:

• Utilized genetically modified mice with whole-body ablation of Hmgcs2.
• Administered a CR diet to these mice and control groups.
• Assessed various metabolic parameters including adiposity, glycemic control, liver autophagy, energy balance, insulin sensitivity, and fuel selection.

Main Results:

• Mice lacking Hmgcs2 largely maintained the metabolic benefits of CR, including changes in adiposity, glycemic control, liver autophagy, and energy balance.
• Sex-specific effects of Hmgcs2 deletion were observed on insulin sensitivity, fuel selection, and adipocyte gene expression, but CR's overall response remained robust.
• Surprisingly, mice adapted to CR showed reduced ketogenesis during fasting periods, indicating a decoupling of CR benefits from high ketone body levels.

Conclusions:

• The primary enzyme for ketone body production, Hmgcs2, is largely dispensable for the majority of CR's metabolic advantages.
• The metabolic benefits associated with long-term CR are not mediated by sustained high levels of ketogenesis.
• CR adaptation leads to a downregulation of ketogenesis during fasting, suggesting alternative pathways are responsible for CR's health-promoting effects.