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Identification of a novel proapoptotic function of resveratrol in fat cells: SIRT1‐independent sensitization to TRAIL‐induced apoptosis
Author(s) -
Mader Isabelle,
Wabitsch Martin,
Debatin KlausMichael,
FischerPosovszky Pamela,
Fulda Simone
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-142943
Subject(s) - resveratrol , apoptosis , microbiology and biotechnology , chemistry , pi3k/akt/mtor pathway , protein kinase b , caspase , gene knockdown , mitochondrion , adipose tissue , biology , pharmacology , programmed cell death , biochemistry
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 μM; TRAIL, >100 ng/ml; combination: 30 μM 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 overex‐pression 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.—Mader, I., Wabitsch, M., Debatin, K.‐M., Fischer‐Posovszky, P., Fulda, S. Identification of a novel proapoptotic function of resveratrol in fat cells: SIRT1‐independent sensitization to TRAIL‐induced apoptosis. FASEB J. 24, 1997–2009 (2010). www.fasebj.org