40 Chapter 2 in obese mice and patients (84,85). KDACs can be classified into four groups (86): Class I comprises KDAC1, 2, 3, and 8; Class II is divided into two sub-groups, IIA (KDAC4, 5, 7, 9) and IIB (KDAC6 and 10); Class III includes the sirtuins, which differ from the other KDACs because they depend on NAD for their deacetylase activity instead of being zinc-dependent like the others; Class IV encompasses KDAC11. Bricambert et al. have described how lower activity of KDACs, KDAC5 and 6 in particular, in white adipose tissue of obese mice and patients correlated with higher levels of pro-inflammatory adipokines (hormones and cytokines secreted by adipocytes) and with impaired glucose uptake (84). However, other studies have shown that sirtuins are probably more important in regulating metabolism (85,87). SIRT1 appears to be most closely linked to the metabolic syndrome and is primarily affected by changes in nutrient conditions like caloric restriction (88) or overnutrition. Cao et al. showed that SIRT1 is intimately connected to insulin resistance by regulating insulin signaling and therefore metabolism of glucose and lipids (89). Yeung et al. reported that SIRT1 inhibited inflammatory responses by deacetylating the p65 subunit of transcription factor Nuclear Factor kappa b (NFkB) (88). NFkb regulates a number of processes involved in inflammation, including induction of the expression of pro-inflammatory genes in many cells (91). A negative correlation between SIRT1 gene expression levels and BMI values of patients (92) was previously shown and this was also associated with more proinflammatory gene expression contributing to insulin resistance. Similarly, SIRT1 levels were also inversely proportional to infiltration of adipose tissue macrophages in human subcutaneous fat (93). This finding was confirmed in vitro by studies showing that SIRT1 inhibits recruitment of macrophages by co-culturing them with SIRT1-deficient adipocytes and showing that the absence of SIRT1 induced their recruitment and a pro-inflammatory phenotype (94). In addition, lower mRNA levels of SIRT1were detected in macrophages of mice fed a high-fat diet that developed obesity (94). These findings on KDACs suggest that combining KDAC activators with antidiabetic drugs could be a more efficient way to treat metabolic syndrome. A wide array of KDAC activators is already available and more specific ones are being developed. Examples of KDAC activators that have been used in the context of metabolic syndrome show beneficial effects by inhibiting expression of proinflammatory cytokines in adipocytes and higher insulin sensitivity and glucose uptake after treatment (83). Importantly, a SIRT1 activator (SRT2104) has entered clinical trials for treatment of DMTII (95). Encouraging findings in mice on a high-fat diet preceded this clinical trial, showing for example that SIRT1 over-
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