ERα/SIRT1 signaling mediates the metabolic regulatory benefits of pterostilbene

Pterostilbene (PTS), a more bioavailable analog of resveratrol (RES), is a promising natural metabolic regulator for improving metabolic health. The metabolic regulatory benefits of RES are believed to be associated with SIRT1 activation. However, the direct activation of SIRT1 by RES was proven to be an in vitro artifact. Here, we demonstrate that PTS is a more potent metabolic regulator than RES. More significantly, we have identified estrogen receptor α (ERα) as the intermediate signaling mediating SIRT1 expression by both RES and PTS. First, RES and PTS function as ERα agonists to stimulate Sirt1 transcription. Second, RES and PTS act as stabilizers of ERα-SIRT1 interaction, blocking ubiquitination and thereby enhancing their protein stability. Third, RES and PTS promote ERα deacetylation, subsequently increasing ERα transactivation. Finally, skeletal muscle-specific ERα knockout attenuates the metabolic regulatory benefits of PTS. Together, our study demonstrates that PTS is a more potent metabolic regulator than RES by activating the ERα/SIRT1 signaling.