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Updated: Mar 25, 2026
Assessment of the Metabolic Effects of Isocaloric 2:1 Intermittent Fasting in Mice
Published on: November 27, 2019
SIRT1 Gain of Function Does Not Mimic or Enhance the Adaptations to Intermittent Fasting
Marie Boutant1, Sameer S Kulkarni1, Magali Joffraud1
1Nestlé Institute of Health Sciences (NIHS), 1015 Lausanne, Switzerland.
Abstract:
Caloric restriction (CR) has been shown to prevent the onset of insulin resistance and to delay age-related physiological decline in mammalian organisms. SIRT1, a NAD(+)-dependent deacetylase enzyme, has been suggested to mediate the adaptive responses to CR, leading to the speculation that SIRT1 activation could be therapeutically used as a CR-mimetic strategy. Here, we used a mouse model of moderate SIRT1 overexpression to test whether SIRT1 gain of function could mimic or boost the metabolic benefits induced by every-other-day feeding (EODF). Our results indicate that SIRT1 transgenesis does not affect the ability of EODF to decrease adiposity and improve insulin sensitivity. Transcriptomic analyses revealed that SIRT1 transgenesis and EODF promote very distinct adaptations in individual tissues, some of which can be even be metabolically opposite, as in brown adipose tissue. Therefore, whereas SIRT1 overexpression and CR both improve glucose metabolism and insulin sensitivity, the etiologies of these benefits are largely different.
Insights
Caloric restriction (CR) and SIRT1 activation both improve metabolic health, but this study shows they achieve benefits through distinct molecular pathways. SIRT1 overexpression did not mimic or enhance the effects of CR in mice.
Area of Science:
- Metabolic research
- Molecular biology
- Aging research
Background:
- Caloric restriction (CR) delays aging and prevents insulin resistance in mammals.
- SIRT1, a deacetylase enzyme, is hypothesized to mediate CR's benefits.
- SIRT1 activation is explored as a potential therapeutic strategy mimicking CR.
Purpose of the Study:
- To investigate if moderate SIRT1 overexpression mimics or enhances metabolic benefits of every-other-day feeding (EODF) in mice.
- To compare the molecular adaptations induced by SIRT1 gain-of-function versus EODF.
- To understand the distinct mechanisms underlying CR-mimetic effects.
Main Methods:
- Utilized a mouse model with moderate SIRT1 overexpression.
- Implemented an every-other-day feeding (EODF) regimen.
- Performed transcriptomic analyses across various tissues.
Main Results:
- SIRT1 transgenesis did not alter the positive effects of EODF on adiposity and insulin sensitivity.
- SIRT1 overexpression and EODF induced distinct tissue-specific adaptations.
- Metabolic adaptations in brown adipose tissue were opposite between SIRT1 transgenesis and EODF.
Conclusions:
- SIRT1 gain-of-function does not replicate the full metabolic benefits of CR (EODF).
- CR and SIRT1 activation confer metabolic improvements through largely different molecular mechanisms.
- Distinct tissue adaptations highlight the complexity of metabolic regulation by SIRT1 and CR.
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