Resveratrol inhibits insulin responses in a SirT1-independent pathway.
Resveratrol mimics calorie restriction to extend lifespan of Caenorhabditis elegans, yeast and Drosophila, possibly through activation of Sir2 (silent information regulator 2), a NAD+-dependent histone deacetylase. In the present study, resveratrol is shown to inhibit the insulin signalling pathway in several cell lines and rat primary hepatocytes in addition to its broad-spectrum inhibition of several signalling pathways. Resveratrol effectively inhibits insulin-induced Akt and MAPK (mitogen-activated protein kinase) activation mainly through disruption of the interactions between insulin receptor substrates and its downstream binding proteins including p85 regulatory subunit of phosphoinositide 3-kinase and Grb2 (growth factor receptor-bound protein 2). The inhibitory effect of resveratrol on insulin signalling is also demonstrated at mRNA level, where resveratrol reverses insulin effects on phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, fatty acid synthase and glucokinase. In addition, RNA interference experiment shows that the inhibitory effect of resveratrol on insulin signalling pathway is not weakened in cells with reduced expression of SirT1, the mammalian counterpart of Sir2. These observations raise the possibility that resveratrol may additionally modulate lifespan through inhibition of insulin signalling pathway, independently of its activation of SirT1 histone deacetylase. Furthermore, the present study may help to explain a wide range of biological effects of resveratrol, and provides further insight into the molecular basis of calorie restriction.
Zhang
Jiandi
J
Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9052, USA. jiandi.zhang@utsouthwestern.edu
D000818:Animals; D002478:Cells, Cultured; D003864:Depression, Chemical; D064429:Fatty Acid Synthases / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D005941:Glucokinase / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034622:RNA Interference; D051381:Rats; D000077185:Resveratrol; D015398:Signal Transduction; D056564:Sirtuin 1; D037761:Sirtuins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology*
D051380:GRB2 Adaptor Protein; D056572:Histone Deacetylase Inhibitors; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D021122:Protein Subunits; D013267:Stilbenes; D064429:Fatty Acid Synthases; D019869:Phosphatidylinositol 3-Kinases; D005941:Glucokinase; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; C447939:SIRT1 protein, human; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol