SIRT1 Gain of Function Does Not Mimic or Enhance the Adaptations to Intermittent Fasting

• Moderate SIRT1 overexpression does not enhance the metabolic effects of EODF
• Transcriptional responses to SIRT1 activation and EODF differ in multiple tissues
• Mitochondrial function is differentially affected by SIRT1 activation and EODF
• SIRT1 and EODF lead to opposite effects on brown adipose tissue function

SummaryCaloric 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.

Graphical AbstractFigure optionsDownload as PowerPoint slide