The role of sirtuin proteins in obesity

Pathophysiology 15 (2008) 103–108

Review

The role of sirtuin proteins in obesity Cheynita F. Metoyer, Kevin Pruitt ∗ Molecular and Cellular Physiology, Feist-Weiller Cancer Center, Louisiana Health Sciences Center School of Medicine in Shreveport, 1501 Kings Highway, Shreveport, LA 71130, USA Received 5 March 2008; received in revised form 28 April 2008; accepted 29 April 2008

Abstract Although the progressive metabolic changes associated with obesity are complex, it is well-recognized that obesity is a risk factor for the development of insulin resistance and type 2 diabetes. Because both obesity and type 2 diabetes are associated with insulin resistance, there is significant interest in defining the mechanistic basis for insulin resistance. Recent studies involving SIRT1, the most intensely studied sirtuin family member, have shown that it regulates many metabolic adaptations linked with obesity. SIRT1 has been shown to regulate the expression of adipokines, repress the activity of factors required for maturation of fat cells, regulate insulin secretion, modulate plasma glucose levels and insulin sensitivity and alter mitochondrial capacity. Moreover, some investigators have suggested that altering SIRT1 activity may be a promising new therapy for type 2 diabetes. In this review we focus on the role of sirtuins in obesity with particular emphasis on the contribution of SIRT1. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Obesity; Sirtuins; SIRT1; PPAR-␥; Calorie restriction

Contents 1. 2. 3. 4. 5. 6.

SIRT1 and metabolic disorders linked with obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SIRT1 and calorie restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SIRT1 and its targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SIRT1 and adipogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulation of metabolism in obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks and implications for therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. SIRT1 and metabolic disorders linked with obesity SIRT1 has been shown to regulate the expression of adiponectin [44,45], repress the activity of PPAR-␥ [40], regulate the secretion of insulin [8], lower plasma glucose levels and improve insulin sensitivity [46] and regulate oxygen consumption and mitochondrial capacity [36,38]. All of these metabolic parameters are frequently deregulated in obesity, and in this review we focus on the role that SIRT1 ∗

Corresponding author. Tel.: +1 318 675 6033; fax: +1 318 675 7393. E-mail address: [email protected] (K. Pruitt).

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plays in the regulation of each. Several excellent reviews have been written on the role of sirtuin proteins in aging [31], adaptive cellular responses [1] and endocrine signaling [58]; however, this review summarizes the most recent studies assessing the role of sirtuin proteins in obesity, type 2 diabetes or pathophysiology linked with these conditions. In order to appreciate the role that SIRT1 plays in the regulation of metabolic adaptations linked with obesity, we will begin with a brief review of the enzymatic properties of SIRT1 (Fig. 1). SIRT1 is an important regulator of chromatin structure and gene expression [43,56] and as such, may prove to be a major

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Fig. 1. Physiological responses of SIRT1 targets. Data show that SIRT1 mediates physiological responses to nutrient availability. The following demonstrates the effects of nutrient restriction which causes the upregulation of SIRT1. SIRT1 then detects changes in NAD+ levels and responds by deacetylating its targets such as FOXO, PGC-1␣, PPAR␥ and NF-␬B. However, a high fat, calorie overloaded, diet would then cause opposing responses, and the dysfunction of these physiological responses are all risk factors or the result of obesity.

determinant of cellular identity via regulation of cell fate decisions [37]. Although chromatin is structurally complex, it can be simply viewed as the highly organized packaging of DNA wrapped around histones [27]. The remodeling of chromatin occurs via diverse epigenetic mechanisms and leads to distinct patterns of gene expression, and SIRT1 is known to regulate both the normal and aberrant expression of these genes [31,43]. Acetylation is a reversible post-translational modification mediated by histone acetyltransferases (HATs). Enzymes that reverse this modification are referred to as histone deacetylases (HDACs) and they have been divided into three classes. We will focus on the class III HDAC gene family, which is referred to as the Silent Information Regulators (or sirtuins). Similar to the class I/II HDACs, sirtuin proteins deacetylate histone and non-histone proteins. However, class III HDACs are quite unique and require NAD+ as a cofactor/substrate which participates in the deacetylation of lysine residues [31]. The products of this reaction are the deacetylated lysine, nicotinamide (vitamin B3) and 2 Oacetyl-ADP-ribose (OAADPr). Nicotinamide is a negative regulator of SIRT1 and mounting evidence suggests that OAADPr serves as a novel signaling molecule or “second messenger” [5]. Because SIRT1 regulates the activity of key molecular switches in the adipogenic program and regulates insulin sensitivity, it is not surprising that it is a key regulator of cell survival in diverse organisms. For example, one of the causes of morbidity and mortality in diabetes mellitus is diabetic nephropathy, which is largely responsible for end stage renal disease. In a model of diabetic nephropathy SIRT1 was shown to be decreased in the diabetic rat kidney [53].

Furthermore, it was demonstrated that intermittent fasting, which prevented the progress of type 1 diabetic nephropathy, caused an increase in the expression of SIRT1 and significantly improved biochemical parameters associated with the development diabetic nephropathy. Additionally, several studies have demonstrated that the adipose-derived hormone, adiponectin, is diminished in both obesity and type 2 diabetes and has anti-inflammatory properties [28]. Interestingly, SIRT1 has been demonstrated to be a major regulator of adiponectin transcription in adipocytes [45] as well as adiponectin secretion [44]. Moreover, SIRT1 protein levels were shown to be significantly lower in epididymal fat tissues from the db/db diabetic mice that have a mutation in the leptin receptor gene and are used frequently as a mouse model for type 2 diabetes [45]. Finally, SIRT1 has been shown to regulate cardiomyocyte contractile function in diabetic mouse models. Recent studies demonstrated that the beneficial effects of fidarestat, which improves cardiomyocyte contractile function in the db/db diabetic obese mice, is dependent on the presence of functional SIRT1 [13]. These studies may provide insights into how SIRT1 regulates cell survival and tissue viability that is linked with type 2 diabetes.

2. SIRT1 and calorie restriction Calorie restriction (CR) is known to reduce age-related chronic diseases and extend lifespan in a number of different organisms [7,32]. Research from a number of groups has clearly demonstrated that SIRT1 regulates longevity. During CR, where the organism has consumed fewer calories

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but still maintained proper nutrition, increases in lifespan have been observed and there is an apparent slowing of age-related deterioration [1,7,33]. Early studies in lower organisms demonstrated that the SIR2 gene (SIRT1 in mammals) was shown to be a one mediator of the effects of CR [25]. Continued investigation on the link between CR and SIRT1 demonstrated that both SIRT1 inhibitors (nicotinamide) and activators can regulate yeast lifespan extension that results from CR [2]. These studies established a link between CR and SIRT1 in yeast and subsequent studies demonstrated a similar link in mammals [6,12]. In work by Cohen et al., rats subjected to CR were shown to have elevated levels of SIRT1 and treatment of human cells with serum from these animals caused an upregulation of SIRT1. SIRT1 was shown to deacetylate the DNA repair factor Ku70 and cause it to inhibit stress-induced apoptotic cell death. Thus, under stress stimuli such as CR, SIRT1 appears to cause cells to remain viable until the source of stress has been eradicated. Studies by Nisoli et al. established yet another link with CR as they demonstrated that it promoted mitochondrial biogenesis by induction of eNOS which corresponded with increased expression of SIRT1 [38]. Finally, studies involving CR in healthy overweight humans showed an increase in SIRT1 mRNA, muscle mitochondrial biogenesis and increased expression of genes encoding proteins involved in mitochondrial function such as eNOS [11]. However, in primary cultures of human myotubes a nitric oxide donor induced mitochondrial biogenesis but failed to induce SIRT1 protein expression. Thus, it is clear that SIRT1 has an impact on metabolic adaptation in response to CR but much remains to be determined about its precise contribution. The extent of obesity that develops over time is a function of calories consumed vs. calories burned and is dependent on the proportion of white adipose tissue (WAT) vs. brown adipose tissue (BAT). In mammals the adipose organ is comprised of both white adipocytes and brown adipocytes, and in most species WAT functions primarily for triglyceride or energy storage and BAT is for energy expenditure that occurs via thermogenesis [21]. With aging, often there is an increase in fat accumulation in the bone marrow, muscle and liver and these changes have been shown to contribute to age-dependent pathophysiology such as osteoporosis, insulin resistance and type 2 diabetes [10,50]. Preadipocytes constitute a significant proportion of adipose tissue and may account for 15–50% of all cells [10] in fat tissue. Using the mouse 3T3-L1 preadipocyte model, SIRT1 was shown to regulate adipogenesis and triglyceride accumulation [40]. In this study SIRT1 was shown to attenuate adipogenesis and increase lipolysis. The authors further demonstrated that SIRT1 stimulated fatty acid mobilization was due to its repression of PPAR-␥ activity [40], a factor that has been shown to be both necessary and sufficient for adipogenesis [14]. Interestingly, SIRT1 has been shown to inhibit differentiation of adipocytes and likewise, beta-catenin and activators of beta-catenin (such as Wnt-1, Wnt-3a and Wnt-10b) also inhibit adipogenesis [19]. Since SIRT1 has been shown to

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silence antagonists of Wnt signaling [43], it will be interesting to further determine the role that SIRT1 and beta-catenin play in the inhibition of adipogenesis. Finally, another sirtuin family member, SIRT2 was shown to regulate adipocyte differentiation through the regulation of Foxo1 activity [24]. This study using the 3T3-L1 model it demonstrated that SIRT2 overexpression inhibited differentiation while SIRT2 reduction promoted adipogenesis.

3. SIRT1 and its targets SIRT1 has been identified as a regulator of oxidative stress and DNA damage. It deacetylates many targets that regulate apoptosis and thereby mediates resistance to stress. CR generates a stress signal and SIRT1 has been shown to act in response and alter metabolism. For example, SIRT1 has been shown to regulate oxygen consumption and the activity of PGC1-␣ and Foxo-3a, two key regulators of metabolism [36]. Increases in SIRT1 mRNA and protein levels in muscle, brain, liver, and fat of rodents results from calorie restriction and fasting [12,47,48]. These increases in SIRT1 levels in these tissues translate into effects on metabolism in response to the alterations in nutrient availability. SIRT1 is a mediator between the changes in nutrient availability and the physiological response, and its dependence on NAD+ levels acts a key sensor for changes in metabolism. The diversity of SIRT1 targets in part explains the complexity of its regulation of metabolism in different tissues. SIRT1 was shown to inhibit the activity of p300 when it deacetylates lysine residues 1020 and 1024 in a critical regulatory domain [9]. Because p300 is expressed in many tissues and plays a major role in the regulation of transcription, this suggests that SIRT1 may critically influence the expression of numerous genes. In muscle cells, SIRT1 has been shown to interact with PCAF and GCN5, two other acetyltransferases, where it plays a role in the formation of a complex with the transcription factor MyoD. SIRT1 deacetylates proteins of the complex when recruited to chromatin as well as lysine residues on histone H3, inhibiting muscle gene expression, and thereby impeding muscle differentiation [20]. Other studies identify SIRT1 activators that positively regulate osteoblast differentiation and decrease adipocyte differentiation, an effect similar to that observed with activation of Wnt signaling [3]. Because mesenchymal/mesodermal stem cells serve as a precursor that can differentiate into osteoblasts, preadipocytes or myoblasts [21], it is important to consider how SIRT1 regulates these cell fate decisions. Age-dependent regulation of SIRT1 was studied and its activity in tissues such as pancreatic ␤ cells was suggested to be important for age-associated metabolic disorders like type 2 diabetes [46]. Additionally, another study implicated the acetylation of the insulin receptor substrate (IRS-2) as an important regulatory feature of insulin signaling and demonstrated that cytoplasmic SIRT1 plays a role in this context [59]. Thus, SIRT1 and its regulation of metabolism, differentiation, and insulin sig-

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naling will likely prove important in understanding insulin resistance and cellular adaptations to stress.

4. SIRT1 and adipogenesis Obese individuals have an increased number and size of adipocytes relative to leaner individuals [15]. Adipogenesis is the mechanism by which the preadipocyte differentiates into a mature adipocyte. One crucial element in regulation of adipogenesis is PPAR-␥. Without PPAR-␥, precursor cells are unable to demonstrate any adipocyte characteristics [14]. Early studies established PPAR-␥ as a critical transcription factor capable of promoting the adipogenic program when over-expressed in mouse fibroblasts, producing fat cells with similar functions to mature adipocytes [54]. Knockout studies reinforced the importance of PPAR-␥ and linked its involvement with both brown and white fat depots [4] and C/EBP␣ was also shown to have critical functions in adipogenesis [18]. Gain of function studies revealed that C/EBP␣ also initiated adipogenesis. However, unlike PPAR-␥, C/EBP was only required for the formation of WAT and not BAT [18]. Notably, PPAR-␥ can initiate adipogenesis in C/EBP deficient mouse fibroblasts but C/EBP could not initiate adipogenesis without PPAR-␥. Therefore, PPAR-␥ is thought to be the dominant player and is also a SIRT1 target. PPAR-␥ interacts with several coregulators. One coactivator is the PPAR-gamma-coactivator 1-␣ (PGC-1␣) which during development regulates BAT development by acting in conjunction with transcription factors like nuclear respiratory factor 1 and PPAR-␥ that control thermogenesis and mitochondrial biogenesis [29,55]. PGC-1␣ also induces pyruvate dehydrogenase kinase4 (PDK4), which inactivates pyruvate dehydrogenase by phosphorylation and prevents pyruvate entry into the TCA cycle. At the transcriptional level, PDK4 is regulated by other factors such as FOXO1, ERR␣, and PPAR␥ that partner with PGC1-␣ [41]. Both SIRT1 and wnt signaling have been shown to attenuate adipogenesis but how the two are linked is not known. While wnt signaling antagonizes adipogenesis by inhibiting the differentiation of mesenchymal stem cells into adipocytes [51], it promotes differentiation into bone or muscle [21]. When Wnt ligands are introduced to preadipocytes or a constitutively active form of ␤-catenin is expressed, adipogenesis is inhibited by preventing induction of PPAR-␥ and C/EBP␣ [34,51]. However, the pathway mediating this inhibition is not yet known. Cyclin D1, a Wnt target gene that has also been shown to be regulated by SIRT1 [43], may be the adipogenic inhibitor, since it has been found to antagonize PPAR␥ [19].

5. Regulation of metabolism in obesity Cells primarily acquire their energy through mitochondria by cellular respiration [57]. Mitochondrial dysfunction

has been linked to a number of diseases in metabolic syndromes [39] and may be a culprit in insulin resistance. Insulin resistance in skeletal muscle correlates with a low ratio of oxidative to glycolytic muscle types, less oxidative capacity in mitochondria and ATP synthesis, as well as a decrease in mitochondrial gene expression [35,39]. Though little is known about SIRT3, a recent report shows that it is a major mitochondrial deacetylase though SIRT3-deficient animals do not appear to have a striking metabolic phenotype [30]. One gene linked with mitochondrial function and biogenesis is the PPAR-␥ coactivator (PGC-1␣) [35,52] which displays tissue specific functions. SIRT1 regulates the activity of both PPAR-␥ and PGC-1␣ [6,49]. In the liver, SIRT1 functions along with PGC-1␣ to mediate the cellular response to changes in nutrient availability. As a result of CR, SIRT1 interacts with and deacetylates PGC –1␣, which regulates gluconeogenesis and glycolysis [48]. The response of the hepatocytes provides other tissues with glucose and represses glycolysis through gene regulation. SIRT1 also deacetylates FOXO1, which promotes gluconeogenic gene transcription [17].

6. Concluding remarks and implications for therapies Mesenchymal stem cells (MSCs) are capable of differentiating into adipocytes, osteoblasts, myoblasts, chondrocytes and connective tissue; however, it is not known what factors control cell fate specification as the MSC differentiates into an adipocyte. What occurs prior to preadipocyte commitment is not clear, but both SIRT1 and Wnt signaling have been shown to regulate the differentiation of preadipocytes into mature adipocytes [21,40,51]. SIRT1 may obviously have beneficial effects in the cellular context with a normal genome where it would make these cells more resistant to stress; however, such prolongation may have a damaging effect from the standpoint of selecting for neoplastic cells during tumor progression. Some adipose tissue, such as breast and thigh adipose tissue is responsive to sex hormones [21], and it will be interesting to determine the role that SIRT1 plays in regulating hormone signaling while it retards adipocyte or muscle differentiation. Recently, a report involving overexpression of SIRT1 in a transgenic mouse model [16] further demonstrated the challenge of understanding the complexity of the regulation of SIRT1 as this study suggested that SIRT1 suppresses polyp formation in the APC/min model. Other studies have shown that SIRT1 is significantly upregulated in mouse and human prostate cancer [23]. Moreover, SIRT1 was significantly elevated in mice with poorly differentiated adenocarcinomas compared with those with less-advanced disease. Additionally, DBC1 (deleted in breast cancer 1) was shown to be an inhibitor of SIRT1 and the DBC1-mediated repression of SIRT1 was shown to lead to increases in p53 acetylation and upregulation of p53-mediated function [60,26]. SIRT1 was also shown to control endothelial angiogenic functions

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during vascular growth [42]. This is an interesting property considering the stress associated with nutritive and oxygen depletion in the core of solid tumors. Will SIRT1 play a role in mediating the survival of select cells within this niche? Finally, Bedalov and colleagues demonstrated that inhibition of SIRT1 activity with cambinol inhibited growth of Burkitt lymphoma xenografts which implicated that inhibitors of SIRT1 may constitute novel anticancer agents [22]. In conclusion, it is clear that CR has many positive effects and SIRT1 appears to be a critical mediator of the cell survival in response to stress. However, the challenge remains in determining whether SIRT1 therapeutics will be effective and safe for the treatment of type 2 diabetes or obesity or whether SIRT1 inhibition will be a viable anti-cancer approach. These are issues that will hopefully be resolved with increased investigation.

References [1] D. Anastasiou, W. Krek, SIRT1: linking adaptive cellular responses to aging-associated changes in organismal physiology, Physiology (Bethesda) 21 (2006) 404–410. [2] R.M. Anderson, K.J. Bitterman, J.G. Wood, O. Medvedik, D.A. Sinclair, Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae, Nature 423 (2003) 181–185. [3] C.M. Backesjo, Y. Li, U. Lindgren, L.A. Haldosen, Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells, J. Bone Miner. Res. 21 (2006) 993–1002. [4] Y. Barak, M.C. Nelson, E.S. Ong, Y.Z. Jones, P. Ruiz-Lozano, K.R. Chien, A. Koder, R.M. Evans, PPAR gamma is required for placental, cardiac, and adipose tissue development, Mol. Cell 4 (1999) 585–595. [5] G. Blander, L. Guarente, The Sir2 family of protein deacetylases, Annu. Rev. Biochem. 73 (2004) 417–435. [6] L. Bordone, D. Cohen, A. Robinson, M.C. Motta, V.E. van, A. Czopik, A.D. Steele, H. Crowe, S. Marmor, J. Luo, W. Gu, L. Guarente, SIRT1 transgenic mice show phenotypes resembling calorie restriction, Aging Cell 6 (2007) 759–767. [7] L. Bordone, L. Guarente, Calorie restriction, SIRT1 and metabolism: understanding longevity, Nat. Rev. Mol. Cell Biol. 6 (2005) 298–305. [8] L. Bordone, M.C. Motta, F. Picard, A. Robinson, U.S. Jhala, J. Apfeld, T. McDonagh, M. Lemieux, M. McBurney, A. Szilvasi, E.J. Easlon, S.J. Lin, L. Guarente, Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells, PLoS Biol. 4 (2006) e31. [9] T. Bouras, M. Fu, A.A. Sauve, F. Wang, A.A. Quong, N.D. Perkins, R.T. Hay, W. Gu, R.G. Pestell, SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1, J. Biol. Chem. 280 (2005) 10264–10276. [10] M.J. Cartwright, T. Tchkonia, J.L. Kirkland, Aging in adipocytes: potential impact of inherent, depot-specific mechanisms, Exp. Gerontol. 42 (2007) 463–471. [11] A.E. Civitarese, S. Carling, L.K. Heilbronn, M.H. Hulver, B. Ukropcova, W.A. Deutsch, S.R. Smith, E. Ravussin, Calorie restriction increases muscle mitochondrial biogenesis in healthy humans, PLoS Med. 4 (2007) e76. [12] H.Y. Cohen, C. Miller, K.J. Bitterman, N.R. Wall, B. Hekking, B. Kessler, K.T. Howitz, M. Gorospe, C.R. de, D.A. Sinclair, Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase, Science 305 (2004) 390–392. [13] F. Dong, J. Ren, Fidarestat improves cardiomyocyte contractile function in db/db diabetic obese mice through a histone deacetylase Sir2dependent mechanism, J. Hypertens. 25 (2007) 2138–2147.

107

[14] S.R. Farmer, Regulation of PPARgamma activity during adipogenesis, Int. J. Obes. (Lond) 29 (Suppl. 1) (2005) S13–S16. [15] S.R. Farmer, Transcriptional control of adipocyte formation, Cell. Metab. 4 (2006) 263–273. [16] R. Firestein, G. Blander, S. Michan, P. Oberdoerffer, S. Ogino, J. Campbell, A. Bhimavarapu, S. Luikenhuis, C.R. de, C. Fuchs, W.C. Hahn, L.P. Guarente, D.A. Sinclair, The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth, PLoS One 3 (2008) e2020. [17] D. Frescas, L. Valenti, D. Accili, Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes, J. Biol. Chem. 280 (2005) 20589–20595. [18] S.O. Freytag, D.L. Paielli, J.D. Gilbert, Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells, Genes Dev. 8 (1994) 1654–1663. [19] M. Fu, M. Rao, T. Bouras, C. Wang, K. Wu, X. Zhang, Z. Li, T.P. Yao, R.G. Pestell, Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment, J. Biol. Chem. 280 (2005) 16934–16941. [20] M. Fulco, R.L. Schiltz, S. Iezzi, M.T. King, P. Zhao, Y. Kashiwaya, E. Hoffman, R.L. Veech, V. Sartorelli, Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state, Mol. Cell 12 (2003) 51–62. [21] S. Gesta, Y.H. Tseng, C.R. Kahn, Developmental origin of fat: tracking obesity to its source, Cell 131 (2007) 242–256. [22] B. Heltweg, T. Gatbonton, A.D. Schuler, J. Posakony, H. Li, S. Goehle, R. Kollipara, R.A. DePinho, Y. Gu, J.A. Simon, A. Bedalov, Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes, Cancer Res. 66 (2006) 4368–4377. [23] D.M. Huffman, W.E. Grizzle, M.M. Bamman, J.S. Kim, I.A. Eltoum, A. Elgavish, T.R. Nagy, SIRT1 is significantly elevated in mouse and human prostate cancer, Cancer Res. 67 (2007) 6612–6618. [24] E. Jing, S. Gesta, C.R. Kahn, SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation, Cell. Metab. 6 (2007) 105–114. [25] M. Kaeberlein, M. McVey, L. Guarente, The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms, Genes Dev. 13 (1999) 2570–2580. [26] J.E. Kim, J. Chen, Z. Lou, DBC1 is a negative regulator of SIRT1, Nature 451 (2008) 583–586. [27] R.D. Kornberg, Y. Lorch, Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome, Cell 98 (1999) 285– 294. [28] F. Lago, C. Dieguez, J. Gomez-Reino, O. Gualillo, Adipokines as emerging mediators of immune response and inflammation, Nat. Clin. Pract. Rheumatol. 3 (2007) 716–724. [29] J. Lin, C. Handschin, B.M. Spiegelman, Metabolic control through the PGC-1 family of transcription coactivators, Cell. Metab. 1 (2005) 361–370. [30] D.B. Lombard, F.W. Alt, H.L. Cheng, J. Bunkenborg, R.S. Streeper, R. Mostoslavsky, J. Kim, G. Yancopoulos, D. Valenzuela, A. Murphy, Y. Yang, Y. Chen, M.D. Hirschey, R.T. Bronson, M. Haigis, L.P. Guarente, R.V. Farese Jr., S. Weissman, E. Verdin, B. Schwer, Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation, Mol. Cell Biol. 27 (2007) 8807–8814. [31] V.D. Longo, B.K. Kennedy, Sirtuins in aging and age-related disease, Cell 126 (2006) 257–268. [32] C.M. McCay, M.F. Crowell, L.A. Maynard, The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935, Nutrition 5 (1989) 155–171. [33] S. Michan, D. Sinclair, Sirtuins in mammals: insights into their biological function, Biochem. J. 404 (2007) 1–13. [34] M. Moldes, Y. Zuo, R.F. Morrison, D. Silva, B.H. Park, J. Liu, S.R. Farmer, Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis, Biochem. J. 376 (2003) 607–613.

108

C.F. Metoyer, K. Pruitt / Pathophysiology 15 (2008) 103–108

[35] V.K. Mootha, C.M. Lindgren, K.F. Eriksson, A. Subramanian, S. Sihag, J. Lehar, P. Puigserver, E. Carlsson, M. Ridderstrale, E. Laurila, N. Houstis, M.J. Daly, N. Patterson, J.P. Mesirov, T.R. Golub, P. Tamayo, B. Spiegelman, E.S. Lander, J.N. Hirschhorn, D. Altshuler, L.C. Groop, PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes, Nat. Genet. 34 (2003) 267–273. [36] S. Nemoto, M.M. Fergusson, T. Finkel, SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC1{alpha}, J. Biol. Chem. 280 (2005) 16456–16460. [37] K.P. Nightingale, L.P. O’Neill, B.M. Turner, Histone modifications: signalling receptors and potential elements of a heritable epigenetic code, Curr. Opin. Genet. Dev. 16 (2006) 125–136. [38] E. Nisoli, C. Tonello, A. Cardile, V. Cozzi, R. Bracale, L. Tedesco, S. Falcone, A. Valerio, O. Cantoni, E. Clementi, S. Moncada, M.O. Carruba, Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS, Science 310 (2005) 314– 317. [39] K.F. Petersen, D. Befroy, S. Dufour, J. Dziura, C. Ariyan, D.L. Rothman, L. DiPietro, G.W. Cline, G.I. Shulman, Mitochondrial dysfunction in the elderly: possible role in insulin resistance, Science 300 (2003) 1140–1142. [40] F. Picard, M. Kurtev, N. Chung, A. Topark-Ngarm, T. Senawong, O.R. hado De, M. Leid, M.W. McBurney, L. Guarente, Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma, Nature 429 (2004) 771–776. [41] H. Pilegaard, P.D. Neufer, Transcriptional regulation of pyruvate dehydrogenase kinase 4 in skeletal muscle during and after exercise, Proc. Nutr. Soc. 63 (2004) 221–226. [42] M. Potente, L. Ghaeni, D. Baldessari, R. Mostoslavsky, L. Rossig, F. Dequiedt, J. Haendeler, M. Mione, E. Dejana, F.W. Alt, A.M. Zeiher, S. Dimmeler, SIRT1 controls endothelial angiogenic functions during vascular growth, Genes Dev. 21 (2007) 2644–2658. [43] K. Pruitt, R.L. Zinn, J.E. Ohm, K.M. McGarvey, S.H. Kang, D.N. Watkins, J.G. Herman, S.B. Baylin, Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation, PLoS Genet. 2 (2006) e40. [44] L. Qiang, H. Wang, S.R. Farmer, Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1-L alpha, Mol. Cell Biol. 27 (2007) 4698–4707. [45] L. Qiao, J. Shao, SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex, J. Biol. Chem. 281 (2006) 39915–39924. [46] K.M. Ramsey, K.F. Mills, A. Satoh, S. Imai, Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in

[47]

[48]

[49]

[50] [51]

[52]

[53]

[54]

[55]

[56]

[57]

[58] [59]

[60]

beta cell-specific Sirt1-overexpressing (BESTO) mice, Aging Cell 7 (2008) 78–88. J.T. Rodgers, C. Lerin, Z. Gerhart-Hines, P. Puigserver, Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways, FEBS Lett. 582 (2008) 46–53. J.T. Rodgers, C. Lerin, W. Haas, S.P. Gygi, B.M. Spiegelman, P. Puigserver, Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1, Nature 434 (2005) 113–118. J.T. Rodgers, P. Puigserver, Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1, Proc. Natl. Acad. Sci. U.S.A. 104 (2007) 12861–12866. C.J. Rosen, M.L. Bouxsein, Mechanisms of disease: is osteoporosis the obesity of bone? Nat. Clin. Pract. Rheumatol. 2 (2006) 35–43. S.E. Ross, N. Hemati, K.A. Longo, C.N. Bennett, P.C. Lucas, R.L. Erickson, O.A. MacDougald, Inhibition of adipogenesis by Wnt signaling, Science 289 (2000) 950–953. L.M. Sparks, H. Xie, R.A. Koza, R. Mynatt, M.W. Hulver, G.A. Bray, S.R. Smith, A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle, Diabetes 54 (2005) 1926–1933. K. Tikoo, D.N. Tripathi, D.G. Kabra, V. Sharma, A.B. Gaikwad, Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53, FEBS Lett. 581 (2007) 1071–1078. P. Tontonoz, E. Hu, B.M. Spiegelman, Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor, Cell 79 (1994) 1147–1156. M. Uldry, W. Yang, J. St-Pierre, J. Lin, P. Seale, B.M. Spiegelman, Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation, Cell Metab. 3 (2006) 333– 341. A. Vaquero, M. Scher, H. Erdjument-Bromage, P. Tempst, L. Serrano, D. Reinberg, SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation, Nature 450 (2007) 440–444. D.C. Wallace, A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine, Annu. Rev. Genet. 39 (2005) 359–407. T. Yang, M. Fu, R. Pestell, A.A. Sauve, SIRT1 and endocrine signaling, Trends Endocrinol. Metab. 17 (2006) 186–191. J. Zhang, The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation, J. Biol. Chem. 282 (2007) 34356–34364. W. Zhao, J.P. Kruse, Y. Tang, S.Y. Jung, J. Qin, W. Gu, Negative regulation of the deacetylase SIRT1 by DBC1, Nature 451 (2008) 587– 590.