SIRT1 Exerts Anti-Inflammatory Effects and Improves Insulin Sensitivity in Adipocytes

Sirtuins, or silent information regulator 2 (Sir2)-related enzymes, were originally defined as a family of NAD+-dependent enzymes that deacetylate lysine residues on various proteins. Certain sirtuins also have ADP-ribosyltransferase activity. The mammalian sirtuins, SIRT1-7, are implicated in a variety of cellular functions, ranging from gene silencing, control of the cell cycle and apoptosis, to energy homeostasis (11). SIRT1 is the closest homolog to Sir2 and the best understood in terms of cellular activity and function. Among the nonhistone cellular substrates of SIRT1 are the tumor suppressor p53 (16, 27), the transcription factor nuclear factor κB (NF-κB) (33), peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC1-α) (21), liver X receptor (15), and the forkhead box O family of transcription factors (32). These genes can be involved in transcriptional control of inflammatory responses, metabolic pathways, cell proliferation, and cell survival. SIRT1 is widely expressed in mammalian tissues and is upregulated by calorie restriction or fasting in the brain, fat, kidney, muscle and liver (6). The broad distribution of SIRT1 in different tissues suggests that its effects on glucose homeostasis are likely to be mediated by tissue-specific factors. In liver, SIRT1 interacts with and deacetylates PGC1-α, leading to increased gluconeogenic gene expression, at least in vitro (21). More recently, in muscle, it has been shown that SIRT1 deacetylation of PGC-1α may be required for activation of mitochondrial fatty acid oxidation (10), which has implications for nutrient adaptation and metabolic diseases. In adipose tissue, SIRT1 represses adipocyte differentiation and genes controlled by the adipogenic regulator PPARγ (20). Overexpression of SIRT1 in 3T3-L1 preadipocytes attenuates adipogenesis, while siRNA-mediated silencing of SIRT1 enhances it. In mature 3T3-L1 adipocytes SIRT1 overexpression triggers lipolysis and loss of fat content. Except for these functions, SIRT1 could have effects on the metabolic syndrome, atherosclerosis, and obesity-related disorders such as type 2 diabetes. For example, treatment of obese insulin-resistant Zucker rats with a SIRT1 activator improves systemic insulin sensitivity without affecting adiposity (19). However, the effect of SIRT1 on insulin signaling has not been elucidated. Several recent studies have implicated SIRT1 in the regulation of inflammatory responses. SIRT1 can deacetylate the tumor suppressor p53, inhibiting its transcriptional activity, resulting in reduced apoptosis in response to various stress stimuli (16, 27). SIRT1 can also inhibit NF-κB, leading to enhanced cell death in response to the inflammatory cytokine tumor necrosis factor alpha (TNF-α) (33). Since increasing evidence indicates that chronic, low-grade inflammation can cause insulin resistance (23), we considered whether SIRT1 could play a role in protection against proinflammatory responses in adipose tissue. In the present study, we show that knockdown of SIRT1 in 3T3-L1 adipocytes leads to enhanced proinflammatory gene expression and increased phosphorylation of JNK, as well as serine phosphorylation of insulin receptor substrate 1 (IRS-1), with subsequent inhibition of insulin signaling events, such as tyrosine phosphorylation of IRS-1, phosphorylation of Akt, ERK, and glucose transport. In contrast, treatment with a SIRT1 activator inhibited 3T3-L1 adipocyte inflammatory pathways and improved insulin signaling. Taken together, these studies indicate that SIRT1 can function as an anti-inflammatory molecule with beneficial effects on insulin action and sensitivity.