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During the initial hours of fasting, the body uses up its glycogen stores as an energy source. Once these glycogen reserves are depleted, the body begins breaking down stored triglycerides and structural proteins. During this stage, glycerol becomes a key substrate for gluconeogenesis, while free fatty acids undergo beta-oxidation to provide energy for tissues, such as skeletal muscle. In the fasting state, the body spares protein breakdown as much as possible to conserve muscle and structural...
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Metabolic States of the Body: The Postabsorptive State01:18

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The postabsorptive state usually starts about four hours after a meal and lasts until the next meal is eaten. During this time, the digestive system stops absorbing nutrients, and the body uses stored energy reserves to maintain stable blood glucose levels.
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During the absorptive state, which lasts approximately four hours after a meal, the body absorbs nutrients from the gastrointestinal tract. The carbohydrates, proteins, and lipids we consume are broken down into monosaccharides, amino acids, and free fatty acids for absorption. While carbohydrates and proteins are absorbed as-is, lipids are absorbed in their broken-down forms and then re-esterified into triglycerides within enterocytes before being packaged into chylomicrons. These absorbed...
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Related Experiment Video

Updated: Jun 13, 2025

Assessment of the Metabolic Effects of Isocaloric 2:1 Intermittent Fasting in Mice
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Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.

Chung-Yang Yeh1,2, Lexie Borgelt1,2, Brynn J Vogt1,2

  • 1Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.

Biorxiv : the Preprint Server for Biology
|June 12, 2025
PubMed
Summary

Caloric restriction (CR) extends health and lifespan, but its benefits are not dependent on ketogenesis. Mice lacking the key enzyme for ketone production still experience CR

Keywords:
BHBcaloric restrictiondietary restrictionketogenesisketonesmetabolic healthmetabolism

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Area of Science:

  • Metabolic research
  • Longevity studies
  • Ketogenesis pathways

Background:

  • Caloric restriction (CR) is a dietary intervention known to extend lifespan and healthspan across various species.
  • CR involves daily feeding followed by a prolonged fasting period, which typically elevates circulating ketone levels.
  • Ketone bodies, particularly β-hydroxybutyrate (βHB), are produced via ketogenesis, a process regulated by the enzyme HMGCS2.

Purpose of the Study:

  • To investigate the role of ketogenesis, specifically βHB production, in mediating the metabolic and health benefits of CR.
  • To determine if HMGCS2, the rate-limiting enzyme in ketogenesis, is essential for CR's effects on metabolism and lifespan.

Main Methods:

  • Utilized genetically engineered mice with whole-body ablation of the HMGCS2 gene to impair ketogenesis.
  • Administered a CR diet to these HMGCS2-deficient mice and compared their metabolic responses to control groups.
  • Assessed key metabolic parameters including adiposity, glycemic control, liver autophagy, energy balance, and insulin sensitivity.
  • Measured fasting βHB levels during the adaptation phase to CR in both HMGCS2-deficient and control mice.

Main Results:

  • Mice lacking HMGCS2 largely maintained the metabolic benefits of CR, including reduced adiposity, improved glycemic control, and altered liver autophagy.
  • CR's positive effects on energy balance and overall physiological adaptation remained robust in the absence of significant ketogenesis.
  • While sex-specific differences in insulin sensitivity and fuel selection were observed, HMGCS2 deficiency did not abolish CR's systemic advantages.
  • Surprisingly, CR-fed mice, upon adaptation, showed diminished ketogenesis during their daily fasting periods, irrespective of HMGCS2 status.

Conclusions:

  • The primary metabolic and health benefits of long-term CR in mice are largely independent of ketogenesis and βHB production.
  • HMGCS2 is dispensable for mediating many of the well-established physiological adaptations to CR.
  • The study challenges the prevailing notion that elevated ketogenesis is a necessary mediator of CR's beneficial effects on health and longevity.