Sirtuins are NAD-dependent deacetylases that are highly conserved from bacteria to human and SIR2 was originally shown to extend lifespan in budding yeast (Imai et al., 2000; Kaeberlein et al., 1999). Since then, sirtuins have been shown to also regulate longevity in other lower organisms, such as flies and worms (Tissenbaum and Guarente, 2001; Rogina and Helfand, 2004). In mammals, there are seven sirtuins (SIRT1-7). All mammalian sirtuins contain a conserved NAD-binding and catalytic domain, termed the sirtuin core domain, but differ in their N- and C-terminal domains (Frye, 2000). They have different specific substrates and biological functions, and are found in various cell compartments. The fact that sirtuins require NAD for their enzymatic activity connects metabolism to aging and aging-related diseases. In this Cell Science at a Glance article, we summarize the recent data related to the role of sirtuins in aging and aging-related diseases, and describe the underlying molecular mechanisms.Sirtuins belong to the class III protein deacetylase family, which are the only histone deactyalses (HDACs) that require NAD for their enzymatic activity (Imai et al., 2000). NAD is an important co-factor for the electron transport chain and is also involved in many enzymatic reactions (Houtkooper et al., 2010). Owing to the characteristic NAD requirement for their enzymatic reaction, the activity of sirtuins is directly linked to the metabolic state in the cell. Initially, yeast SIR2 was discovered as a histone deacetylase, but mammalian sirtuins have also various non-histone protein substrates. The deacetylation reaction of sirtuins consists of two steps. In the first, sirtuins cleave NAD and produce nicotinamide (NAM), and in the second step the acetyl group is transferred from the substrate to the ADP-ribose moiety of NAD to generate O-acetyl-ADP ribose and the deacetylated substrate (Tanner et al., 2000). Although most of sirtuins have deacetylase activity, SIRT4 has been shown to have only ADP-ribosyltransferase activity, whereas SIRT1 and SIRT6 have both deacetylation and a relatively weak ADP-ribosyltransferase activity (Haigis et al., 2006; Imai et al., 2000; Liszt et al., 2005; Michishita et al., 2008). Interestingly, the generated NAM is an endogenous inhibitor of sirtuins and is usually converted to nicotinamide mononucleotide (NMN) by the NAD salvage pathway enzyme, nicotinamide phosphoribosyl-transferase (Nampt). Subsequently, nicotinamide mononucleotide adenyltransferase (Nmnat) regenerates NAD from NMN (Houtkooper et al., 2010) (see poster). Recent studies suggest that NAD biosynthesis critically regulates the activity of sirtuins. For example, Nampt-mediated NAD biosynthesis controls SIRT1 activity in several tissues; and SIRT3, SIRT4 and SIRT5 are also regulated by NAD biosynthesis in response to nutrient stress (Nakagawa et al., 2009; Revollo et al., 2007; Yang et al., 2007). Nampt also mediates the production of tumor necrosis factor α (TNFα) in a SIRT6 dependent manner (Van Gool et al., 2009). Additionally, NAD biosynthesis is linked to the circadian clock cycle, because Nampt is regulated by a complex consisting of the circadian locomotor output cycles kaput (CLOCK), brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) and SIRT1, and in turn regulates SIRT1 activity through NAD (Nakahata et al., 2009; Ramsey et al., 2009).As well as yeast SIR2, its mammalian homolog SIRT1 was shown to be able to deacetylate histones and preferentially deacetylates lysine (K) residue 9 of histone 3 (H3K9) and lysine 16 of histone 4 (H4K16) in vitro (Imai et al., 2000; Vaquero et al., 2004). SIRT1-deficient mouse embryonic fibroblasts (MEFs) also accumulate hyperacetylated histones, thereby promoting heterochromatin formation and transcription repression (Vaquero et al., 2007; Wang et al., 2008). SIRT1 deletion in MEFs also leads to histone H3K9 hypomethylation (Vaquero et al., 2007). SIRT1 directly binds to the histone methyltransferase Suv39h1 and upregulates its methyltransferase activity by deacetylating lysine residue 266, which resides in the SET domain of Suv39h1. SIRT1 also interacts with linker histone H1b and deacetylates its lysine 26 (H1K26) (Vaquero et al., 2004). In response to oxidative stress, SIRT1 is redistributed and so binds to acetylated histone H1K26, which leads to the repression of various set of genes. Interestingly, the transcriptional repression pattern is similar to that observed in the mouse brain with aging (Oberdoerffer et al., 2008). Thus, it can be speculated that SIRT1 is responsible for aging-dependent global transcriptional changes through chromatin modification.SIRT1 regulates various metabolic processes that allow the cell to adapt to nutrient stress and has a pivotal role in aging-related metabolic diseases. In response to fasting, SIRT1 modulates gluconeogenesis in the liver through deacetylation of important factors, such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), forkhead box protein O1 (FOXO1) and cAMP response element-binding (CREB)-regulated transcription coactivator 2 (CRTC2) (Brunet et al., 2004; Liu et al., 2008; Motta et al., 2004; Rodgers et al., 2005). In the early phase of fasting, CRTC2 is activated through its acetylation by the co-activator CBP/p300, which then promotes transcription of gluconeogenic genes. If fasting is prolonged, SIRT1 deacetylates both CRTC2 and FOXO1, which leads to a switch from activation of early gluconeogenic genes through CRTC2 to the activation of genes involved in the late phase of gluconeogenesis through FOXO1 (Liu et al., 2008). Deacetylation of PGC-1α by SIRT1 not only controls gluconeogenesis, but also fatty acid oxidation in coordination with peroxisome proliferator-activated receptor alpha (PPARα) (Purushotham et al., 2009). PGC1α also regulates mitochondria biogenesis and oxidative phosphorylation, and it...

Adipose tissue resident macrophages have important roles in the maintenance of tissue homeostasis and regulate insulin sensitivity for example by secreting pro-inflammatory or anti-inflammatory cytokines. Here, we show that M2-like macrophages in adipose tissue regulate systemic glucose homeostasis by inhibiting adipocyte progenitor proliferation via the CD206/TGFβ signaling pathway. We show that adipose tissue CD206⁺ cells are primarily M2-like macrophages, and ablation of CD206⁺ M2-like macrophages improves systemic insulin sensitivity, which was associated with an increased number of smaller adipocytes. Mice genetically engineered to have reduced numbers of CD206⁺ M2-like macrophages show a down-regulation of TGFβ signaling in adipose tissue, together with up-regulated proliferation and differentiation of adipocyte progenitors. Our findings indicate that CD206⁺ M2-like macrophages in adipose tissues create a microenvironment that inhibits growth and differentiation of adipocyte progenitors and, thereby, control adiposity and systemic insulin sensitivity.