SRT1720 behaves as a mimetic for calorie restriction and improves glucose homeostasis and insulin sensitivity. [a] Flow diagram depicting the downstream effects of Sirt1 activation by the compounds SRT501 and SRT1720 in DIO mouse livers after 3 days of treatment. Green – measured and observed increase. Yellow – statistically significant hypothesized increase. White – a given process (e.g. inflammation) supported by statistically significant hypotheses. Blue – hypothesized decrease in activity or abundance. Non-directional lines indicate similarity between SRT501, SRT1720 and resveratrol treatment and the effects of calorie restriction. Lines with arrowheads indicate causal activation; lines with bars indicate causal inhibition. The direction of the arrow in boxes indicates whether a process, hypothesis or observation shows an increase or decrease with SRT501 or SRT1720. Numbers in brackets indicate the number of RNA state changes supporting that hypothesis. [b] Table of processes activated or attenuated in response to SRT501 and SRT1720 treatment and the statistically significant hypotheses that support them. [c] Scatter plot obtained by graphing fold changes of significant probe sets supporting the increased CR hypothesis in the SRT1720 dataset comparison versus the SRT501 dataset comparison. [d] Fasted plasma glucose levels were improved following treatment with either SRT501 (1000 mg/kg) or SRT1720 (100 mg/kg) as compared to vehicle treated DIO mice (* p < 0.05). Fed plasma insulin following treatment with SRT501 (1000 mg/kg) or SRT1720 (100 mg/kg) was significantly reduced (*p < 0.05) as compared to vehicle treated control DIO mice. Error bars represent standard error of the mean.