Resveratrol (RSV) is a naturally occurring polyphenol that has been found to 
exert antioxidant, anti-inflammatory, and neuroprotective properties. However, 
how RSV exerts its beneficial health effects remains largely unknown. Here, we 
show that RSV inhibits insulin- and leucine-stimulated mTOR signaling in C2C12 
fibroblasts via a Sirt1-independent mechanism. Treating C2C12 cells with RSV 
dramatically inhibited insulin-stimulated Akt, S6 kinase, and 4E-BP1 
phosphorylation but had little effect on tyrosine phosphorylation of the insulin 
receptor and activation of the p44/42 MAPK signaling pathway. RSV treatment also 
partially blocked mTOR and S6 kinase phosphorylation in TSC1/2-deficient mouse 
embryonic fibroblasts, suggesting the presence of an inhibitory site downstream 
of TSC1/2. Knocking out PDK1 or suppressing AMP-activated protein kinase had 
little effect on leucine-stimulated mTOR signaling. On the other hand, RSV 
significantly increased the association between mTOR and its inhibitor, DEPTOR. 
Furthermore, the inhibitory effect of RSV on leucine-stimulated mTOR signaling 
was greatly reduced in cells in which the expression levels of DEPTOR were 
suppressed by RNAi. Taken together, our studies reveal that RSV inhibits 
leucine-stimulated mTORC1 activation by promoting mTOR/DEPTOR interaction and 
thus uncover a novel mechanism by which RSV negatively regulates mTOR activity.