SIRT1 is a prominent member of a family of
NAD(+)-dependent
enzymes and affects a variety of cellular functions ranging from gene silencing, regulation of the cell cycle and apoptosis, to energy homeostasis. In mature adipocytes,
SIRT1 triggers lipolysis and loss of fat content. However, the potential effects of
SIRT1 on
insulin signaling pathways are poorly understood. To assess this, we used RNA interference to knock down
SIRT1 in 3T3-L1 adipocytes.
SIRT1 depletion inhibited
insulin-stimulated
glucose uptake and GLUT4 translocation. This was accompanied by increased phosphorylation of JNK and
serine phosphorylation of
insulin receptor substrate 1 (IRS-1), along with inhibition of
insulin signaling steps, such as
tyrosine phosphorylation of IRS-1, and phosphorylation of Akt and ERK. In contrast, treatment of cells with specific small molecule
SIRT1 activators led to an increase in
glucose uptake and
insulin signaling as well as a decrease in
serine phosphorylation of IRS-1. Moreover, gene expression profiles showed that
SIRT1 expression was inversely related to inflammatory gene expression. Finally, we show that treatment of 3T3-L1 adipocytes with a
SIRT1 activator attenuated
tumor necrosis factor alpha-induced
insulin resistance. Taken together, these data indicate that
SIRT1 is a positive regulator of
insulin signaling at least partially through the anti-inflammatory actions in 3T3-L1 adipocytes.