Identification of a novel proapoptotic function of resveratrol in fat cells: SIRT1-independent sensitization to TRAIL-induced apoptosis.

The phytochemical resveratrol has recently gained attention for its protection against metabolic disease and for extension of life span, which have been linked to its metabolic effects and SIRT1 activation in fat cells. However, little is known about the effect of resveratrol on fat cell apoptosis. Here, we identify a novel, SIRT1-independent mechanism by which resveratrol regulates fat cell numbers. We demonstrate for the first time that resveratrol enhances TNF-related apoptosis-inducing ligand (TRAIL)- or CD95-induced apoptosis of human preadipocytes in a highly synergistic manner (EC(50) at 72 h: resveratrol, >300 microM; TRAIL, >100 ng/ml; combination: 30 microM resveratrol and 10 ng/ml TRAIL, combination index 0.4). Similar results in primary human preadipocytes prepared from subcutaneous white adipose tissue and mature human adipocytes underline the relevance to human physiology. Mechanistic studies reveal that resveratrol inhibits PI3K-driven phosphorylation of Akt, leading to increased Bax activation, loss of mitochondrial membrane potential, cytochrome c release, and caspase-dependent apoptosis. The synergistic interaction of resveratrol and TRAIL depends on the intrinsic apoptosis pathway and caspases, since Bcl-2 overexpression and the caspase inhibitor zVAD.fmk inhibit apoptosis, whereas knockdown of SIRT1 by RNA interference has no effect. The discovery of this novel activity of resveratrol significantly advances the knowledge of fat tissue regulation by resveratrol and has important implications for its use in metabolic and age-related diseases.