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. 2009 Mar 10;3:31.
doi: 10.1186/1752-0509-3-31.

Small Molecule Activators of SIRT1 Replicate Signaling Pathways Triggered by Calorie Restriction in Vivo

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Free PMC article

Small Molecule Activators of SIRT1 Replicate Signaling Pathways Triggered by Calorie Restriction in Vivo

Jesse J Smith et al. BMC Syst Biol. .
Free PMC article

Abstract

Background: Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation.

Results: Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet.

Conclusion: CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.

Figures

Figure 1
Figure 1
Chemical Structures of SRT501-resveratrol and SRT1720.
Figure 2
Figure 2
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.
Figure 3
Figure 3
SRT501 and SRT1720 treatment leads to increased metabolism and mitochondrial biogenesis. [a] Flow diagram of a network depicting statistically significant hypotheses supporting increased metabolism and mitochondrial biogenesis in DIO mouse livers after 3 days of treatment. Numbers in brackets indicate the number of RNA state changes supporting that hypothesis. taof – transcriptional activity of a given protein. [b] Scatter plot obtained by graphing fold changes of significant probe sets supporting the increased taof(Pparα) hypothesis in the SRT1720 dataset comparison versus the SRT501 dataset comparison. [c] Scatter plot obtained by graphing fold changes of significant probe sets supporting the increased taof(Ppargc1α) hypothesis in the SRT1720 dataset comparison versus the SRT501 dataset comparison. [d] C2C12 myotubes were treated with vehicle, SRT501 or SRT1720 at the indicated concentrations for 48 hours. Citrate Synthase activity was measured in lysates as a marker for mitochondrial function. p values were measured using an unpaired, 2-tailed t test. n = 3 replicates per group for compound treatments and n = 6 replicates for vehicle treatment. Error bars represent standard error of the mean. (**p < 0.01, ***p < 0.001). [e] NCI-H358 cells were treated with vehicle, SRT501 (50 μM) or SRT1720 (1 μM) for 48 hours. Cellular ATP levels were then measured as marker for mitochondrial function. P values were measured using an unpaired, 2-tailed t test. n = 3 replicates per group. Error bars represent standard error of the mean (*p < 0.005).
Figure 4
Figure 4
SRT501 and SRT1720 treatment leads to decreased inflammatory signaling. [a] Flow diagram of a network depicting statistically significant hypotheses supporting decreased pro-inflammatory signaling in DIO mouse livers after 3 days of treatment. Protein names lacking the taof prefix indicate decreased abundance, e.g. decreased abundance of Tnfα ligand leads to decreased taof(NF-κB complex). [b] Scatter plot obtained by graphing fold changes of significant probe sets supporting the decreased taof(NF-κB complex) hypothesis in the SRT1720 dataset comparison versus the SRT501 dataset comparison. [c] RAW 264.7 macrophages were treated with vehicle (0.2% DMSO), SRT501 (10 and 20 μM) or SRT1720 (1 and 2 μM) for 1 hour. Subsequently, TNFα secretion was induced by addition of LPS at 100 ng/ml for 1 hour. Cell Supernatants were collected and TNFα levels were measured by ELISA. TNFα levels are depicted as a percent of vehicle control (P.O.C.). P values were measured using an unpaired, 2-tailed t test. n = 3 replicates per group for each compound treatment. n = 8 replicates per group for each vehicle treatment. Error bars represent standard error of the mean. (*p < 0.05, **p < 0.005).

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