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.