Resveratrol is known to be a SIRT1-activator. However, various effects of resveratrol are not explained by activation of SIRT1 alone. We found that resveratrol is an activator not only for PPARα and γ , but also for PPARβ/δ (Figure 1B) in this report. Moreover, vaticanol C, a resveratrol tetramer, is an activator for PPARα and β/δ in cell-based reporter assays (Figure 1B), which is confirmed by induced expression of PPAR-responsive genes in wild-type, but not PPARα-knockout, mice (Figure 3A). At lower concentrations of 1.25-5 μM, vaticanol C showed higher PPARα-agonistic activity than resveratrol. However, at 10 μM, resveratrol showed higher activity than vaticanol C (Figure 1A), and this activity of resveratrol was dose-dependent, at less than 40 μM (data not shown). Previously, we found that expression of COX-2, an inducible key enzyme for prostaglandin synthesis, was regulated by 15d-PGJ2, a natural ligand for PPARγ . Interestingly, vaticanol C as well as resveratrol  suppressed the expression of COX-2 in several kinds of tumor cell lines (data not shown) whereas vaticanol C is not an activator for PPARγ.
Vaticanol C did not activate SIRT1 whereas resveratrol activated SIRT1 by the assay utilizing a fluorophore-containing peptide (Figure 2C). Recent report showed that this assay was not suitable to direct measurement of the SIRT1 activity and that resveratrol did not activate SIRT1 in the assay without the fluorophore-containing peptide . Therefore, by the different assay system, we may confirm that vaticanol C is not activator for SIRT1. Taken together, vaticanol C is a dual activator for PPARα and β/δ, whereas resveratrol is a triple activator for PPARα, β/δ and γ, indicating that vaticanol C is thought to be differently effective on lifestyle-related diseases, compared with resveratrol.
A resveratrol dimer, ε-viniferin has radical-scavenging activity, but does not have agonistic activity for PPARs or SIRT1, which differs from resveratrol and vaticanol C (Figure 2). These differences indicate the importance of the structure of these chemicals. Concerning the binding pocket of PPARα, the molecular sizes of resveratrol and vaticanol C are smaller and larger than those of synthetic PPAR agonists such as fenofibrate, respectively. Resveratrol but not vaticanol C activates PPAR γ, indicating the importance of the structure of these molecules in the binding pocket of PPARs. It was reported that a single amino acid, which was Tyr in PPARα and His in PPARγ, imparted subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands . We need more experimental data to discuss about these points including the possibility of indirect activation of PPARs by resveratrol and vaticanol C.
There are distinct expression patterns of PPAR-responsive genes in the liver and skeletal muscle, indicating that PPAR-responsive genes are controlled in a tissue-specific manner (Figure 3A). In this context, especially in skeletal muscles, vaticanol C upregulates expression of PPARβ/δ-responsive genes, such as UCP3 and PDK4, in the wild-type, but not PPARα-knockout mice, indicating that PPARα is also involved in the expression of PPARβ/δ-responsive genes.
Resveratrol has been reported to prevent body weight gain with a HF diet . No such effect on body weight was observed after vaticanol C treatment. We found that 129SV mice used in our study showed milder body weight gain with a HF diet, versus the C57/black strain mice used in several reports. This difference on body weight gain will be due to the different strains between 129SV and C57/black. These genetic differences are also usual common in human genomes. To address these questions, we are studying on the molecular mechanism involved in the physiological differences between 129SV and C57/black mice.