Caloric restriction rapidly alters lipogenic transcriptions factors in the liver independent of changes in SIRT1 or IGF‐1

Caloric restriction (CR) extends maximal lifespan and retards aging by mechanisms that remain unclear. Our goal was to determine whether putative mediators of the anti‐aging effects of CR change with a time course rapid enough to explain CR‐induced changes in key transcription factors and enzymes. Plasma levels of insulin, glucose, and IGF‐1 were measured in male C57Bl/6 mice (9/group) that had undergone 0, 1, 4 or 16 weeks of caloric restriction (9 Kcal/day, approximately 66% of ad lib. intake). SIRT1, a histone deacetylase implicated in the anti‐aging effects of CR, was assessed via Western blot. The amount of mRNA for PPAR γ , SREBP‐1C, fatty acid synthase and acetyl‐CoA carboxylase were quantified in the liver using real time RT‐PCR. While these lipogenic transcription factors and enzymes were decreased to less than 33% of baseline in the liver by 16‐weeks of CR (p<0.05), neither IGF‐1 nor SIRT1 was significantly altered from baseline at any timepoint. However, insulin decreased from 1.7 ± 0.4 ng/ml at baseline to 0.7 ± 0.1 after only 1 week of CR (p<0.05) and continued to decline after 4 and 16 weeks of CR (0.6 ± 0.2 and 0.5 ± 0.1 ng/ml, respectively). This fall in insulin was concomitant with a significant decline in plasma glucose indicating a very rapid whole body insulin sensitization. We conclude that CR‐induced changes in lipogenic transcription factors and enzymes occur too rapidly to be explained by changes in SIRT1 or IGF‐1, and are more likely linked to changes in insulin sensitivity. This study was supported by NIH/NIA AG00908