Review

10.1517/14728222.11.10.1329 © 2007 Informa UK Ltd ISSN 1472-8222 1329

1. Introduction

2. Targeting PGC-1α pathway

for the treatment of metabolic

diseases

3. Expert opinion and conclusion

Oncologic, Endocrine & Metabolic

Targeting PGC-1 a to control energy homeostasis Zhidan Wu & Olivier Boss Novartis Institutes for BioMedical Research, Inc. , 100 Technology Square , Cambridge, MA 02139 , USA, and Sirtris Pharmaceuticals, Inc., Cambridge, MA 02139, USA

The prevalence of Type 2 diabetes is increasing at an alarming rate in most parts of the world. Effective therapeutic drugs are urgently needed, not only to control the disease but also to prevent or delay its progression. Therapies that target the underlying pathogenesis could, in theory, hold such potential. Recent evidence strongly suggests that impaired mitochondrial function is part of the underlying pathogenesis of insulin resistance and Type 2 diabetes. Peroxisome proliferator-activated receptor γ co-activator-1 α (PGC-1 α ) is a transcription co-activator that plays a key role in regulating mitochondrial biogenesis and energy metabolism in multiple tissues. Thus, improvement and restoration of mitochondrial function and oxidative capacity through activation of PGC-1 α could provide new treatments for metabolic diseases. A diverse array of proteins has been shown to regulate PGC-1 α transcription and/or activity, some of which represent promising targets for pharmaceutical intervention.

Keywords: estrogen-related receptor α , insulin resistance , mitochondrial biogenesis , oxidative phosphorylation , peroxisome proliferator-activated receptor γ co-activator-1 α , Type 2 diabetes , sirtuin 1

Expert Opin. Ther. Targets (2007) 11(10):1329-1338

1. Introduction

The prevalence of Type 2 diabetes (T2D) is increasing rapidly in most parts of the world. It is predicted that there will be > 300 million cases of diabetes worldwide by 2025 and the large majority of these cases are expected to be T2D, which is characterized by both insulin resistance and insufficient insulin secretion from pancreatic β -cells [1] . Diabetes is not only one of the leading causes of death in the US, but it is also associated with and/or contributes to various complications, such as cardiovascular disease, blindness, renal disease and infection [2,3] . Unfortunately, drugs used at present to treat diabetes have little, if any, impact on the progression of the disease. On average, patients will progress to using insulin as a form of therapy in 10 years when oral agents fail to provide adequate glycemic control. Thus, new effective drugs are needed urgently, not only to control the disease, but also to prevent its progression. Therapies that can restore insulin sensitivity and/or preserve pancreatic β -cell function are believed to be more effective either as stand-alone treatments or in combination with existing drugs.

In the past decade, intensive research has advanced our understanding of the underlying pathogenesis of T2D. The modern sedentary life style and excess calorie intake (chronic, positive energy balance) have made obesity, which is the highest risk factor for insulin resistance and T2D, an epidemic [4,5] . The development of insulin resistance necessitates the increased production of insulin by the pancreatic β -cells to maintain normal blood glucose levels. T2D develops when pancreatic β -cells fail to keep up with the increased needs for insulin in the face of worsening insulin resistance. A large body of literature implicates dysregulation of fatty acid metabolism [6,7,11] , adipose tissue inflammation [12,13] , increased ER stress [14] ,

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and mitochondrial dysfunction [15] as instrumental to the development of insulin resistance and T2D. Results from recent studies showed reduced mitochondrial content in skeletal muscle of obese and Type 2 diabetic patients [16] . In addition, the muscle ATP synthesis rate, which is indicative of mitochondrial function, was shown to be reduced in insulin resistant subjects [17,18] . In muscle biopsies from Type 2 diabetic patients, the expression levels of genes involved in oxidative phosphorylation (OXOPHOS) were found to be reduced [19,20] . In contrast, exercise training, known to have a beneficial effect on insulin sensitivity and glycemic control, promotes mitochondrial biogenesis and enhances oxidative capacity in muscle [21] . Thus, restoration or improvement of mitochondrial function and oxidative capacity in muscle could be a therapeutic approach to treat insulin resistance and T2D. As the transcription co-activator, peroxisome-proliferator-activated receptor-γ co-activator 1 α (PGC-1 α ) is a key component in the regulation of mitochondrial biogenesis, oxidative capacity and energy metabolism [22,23] , pharmaceutical intervention through the activation of PGC-1 α , either directly or indirectly, represents a promising approach to the development of treatment. The rationales of targeting the PGC-1 α pathway to improve mitochondrial function and the potential drug targets are discussed in this review.

1.1 PGC-1 a : a master regulator of mitochondrial biogenesis PGC-1 α was discovered in 1998 as a cold-inducible co-activator of PPAR- γ that promotes adaptive thermo genesis, a physiologic process that dissipates energy as heat [24] . Adaptive thermogenesis occurs in brown adipose tissue (BAT) and in skeletal muscle in rodents and accounts for a significant portion of energy expenditure. Adaptive thermo-genesis is accompanied by stimulation of mitochondrial biogenesis, increased fatty acid oxidation and the uncoupling of OXOPHOS. PGC-1 α plays an important role in the regulation of mitochondrial biogenesis in response to environmental stimuli [10] ; ectopic expression of PGC-1 α also strongly promotes mitochondrial biogenesis and cellular respiration in a variety of cell types [23] . In vivo studies show that the muscle-specific PGC-1 α transgenic mice have increased mitochondrial biogenesis and oxidative capacity in muscle [25] . In addition, PGC-1 α knockout (KO) mice have reduced mitochondrial function and oxidative capacity in muscle [28] , thus supporting an essential role for PGC-1 α in normal muscle mitochondrial function. Mechanistically, PGC-1 α induces mitochondrial biogenesis by increasing the expression and activity of the key transcription factors, including nuclear respiratory factor-1 (NRF-1) and -2, mitochondrial transcription factor A (mtTFA) and estrogen related-receptor α (ERR α ), which govern the expression of mitochondrial proteins encoded by either the nuclear or mitochondrial genome in a coordinative manner [8,10,26] . Both gain-of-function and loss-of-function

studies indicate that PGC-1 α is a key regulator of adaptive mitochondrial biogenesis and essential for normal mitochondrial function.

1.2 PGC-1 a modulates various metabolic pathways in peripheral metabolic tissues Intensive research on PGC-1 α has shown that this co-activator plays multifaceted roles in regulating a number of metabolic pathways in various tissues. In BAT, PGC-1 α promotes adaptive thermogenesis [24] . Expression of PGC-1 α in BAT is markedly induced by cold temperature and thermogenic stimuli, such as thyroid hormone T3, β -adrenergic agonists and cyclic AMP [24] . Mechanistically, PGC-1 α increases the transcription of uncoupling protein-1 (UCP-1) by enhancing PPAR γ transcriptional activity [24] . Ectopic expression of PGC-1 α in white adipocytes specifically increases the expression of BAT-specific genes, such as UCP-1 [24] . In vivo studies with PGC-1 α null mice show that these mice are cold-sensitive due to a reduced thermogenic capacity [28] .

Skeletal muscle is an important tissue in glucose and lipid metabolism. Ectopic expression of PGC-1 α in muscle cells increases mitochondrial number, the expression levels of mitochondrial proteins, fatty acid oxidation and cellular respiration [8-10] . In addition, PGC-1 α expression increases the expression of the insulin-sensitive glucose transporter glucose transporter 4 (GLUT4) and enhances glucose uptake in muscle cells [29] . Muscle-specific PGC-1 α transgenic mice have increased mitochondrial number and display a conversion of type IIb glycolytic muscle fibers into oxidative, type I muscle fibers [25] . Type I fibers are rich in mitochon-dria and preferentially use fatty acids as fuel. The proportion of type I fibers in muscle is increased by endurance training. Interestingly, transgenic mice overexpressing PGC-1 α in muscle display increased resistance to fatigue, whereas PGC-1 α KO mice have reduced tissue mitochondrial content, impaired muscle performance and exercise capacity [28,30] . The impact of a PGC-1 α deficiency on glucose homeostasis is intriguing. The KO mice generated by Lin et al. [28] are hyperactive, resulting in increased energy expenditure, decreased bodyweight and improved insulin sensitivity. The KO mice generated by Leone et al. [30] are also more sensitive to insulin compared with the control mice when fed with a high-fat diet. The latter results are surprising, given the recent findings of the strong correlation between reduced mitochondrial function and insulin resistance in humans. However, it is certainly possible that other metabolic regulatory mechanisms are disturbed in these PGC-1 α KO mice. Therefore, the tissue-specific PGC-1 α KO mice will be more appropriate in vivo models for addressing the role of PGC-1 α in energy metabolism. Collectively, the in vitro and in vivo studies indicate that PGC-1 α plays an important role in muscle mitochondrial function and oxidative capacity, whereas the role of PGC-1 α in glucose homeostasis warrants further investigation using tissue-specific KO mice.

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Gluconeogenesis is a key metabolic pathway in the liver and PGC-1 α expression in this tissue is increased after fasting [31] . Interestingly, glucagon and glucocorticoids strongly stimulate PGC-1 α expression in hepatocytes [31] . Furthermore, induction of PGC-1 α in turn induces the expression of gluconeogenic genes expression by co-activating a number of transcription factors, most notably hepatocyte nuclear factor 4 α (HNF4 α ) and Forkhead box O1(Foxo1) [32,33] . Indeed, PGC-1 α expression is markedly elevated in the livers from diabetic mice that have increased gluconeogenesis [31] . Recent studies have identified additional players, sirtuin 1 (SIRT1) and GCN5 (General control of amino acid and synthesis yeast homolog-like 2), which reg-ulate gluconeogenesis by modulating PGC-1 α activity [34,35] . PGC-1 α has also been shown to have a role in regulating energy metabolism and insulin secretion in pancreatic β cells [36] . The expression of PGC-1 α is elevated in islets from ob/ob mice and Zucker diabetic fatty rats, which have increased insulin secretion. In contrast, overexpression of PGC-1 α in insulinoma cell line (INS-1) cells and isolated islets suppressed glucose-stimulated insulin secretion and the expression of GLUT2 and glucokinase [36] . The specific transcription factors through which PGC-1 α achieves the suppression of glucose-stimulated insulin secretion remains to be determined.

In the heart, PGC-1 α is implicated in controlling cardiac energy metabolic pathways during development and in response to physiologic stresses. Cardiac PGC-1 α expression is induced after birth as the heart turns towards mitochon-drial fatty acid oxidation as its main energy source [37] . PGC-1 α is also induced after fasting in the heart when fat oxidation is markedly increased for ATP production. Mechanistically, PGC-1 α controls the expression of cardiac fatty acid oxidation and respiration genes through co-activation of peroxisome proliferator-activated receptor α and estrogen related receptor α [38] . Loss-of-function studies using PGC-1 α KO mice show that these mice display a modest diminution in cardiac function [30] . In addition, the ability to increase work output in response to chemical or electrical stimulation is severely blunted in the hearts isolated from the KO mice [39] , thus suggesting that PGC-1 α plays an important role in regulating cardiac energy metabolism.

1.3 Regulation of PGC-1 a in health and disease 1.3.1 Pathways and factors regulating PGC-1 a transcription and activity PGC-1 α expression and activity are regulated by physiologic and environmental stimuli in a tissue-specific fashion. PGC-1 α transcription is induced by cold temperatures in BAT and muscle, and by fasting in liver and heart [24,31,37] . In addition, PGC-1 α levels are increased by exercise and calorie restriction in muscle [40-42] . This tissue-specific regula-tion of PGC-1 α can, in turn, induce specific metabolic processes in different tissues. Several signaling pathways and proteins have been implicated in the regulation of

PGC- α expression and/or activity through transcriptional and post-transcriptional modifications of this protein. In particular, the cAMP pathway is key in activating PGC-1 α transcription in many tissues through promoting the binding of cAMP response element binding protein (CREB) or activating transcription factor 2 (ATF-2) to the PGC-1 α promoter, thus activating its transcription. The activation of PGC-1 α in BAT by β -adrenergic agonists is mediated through ATF-2. PGC-1 α transcription is activated by glucagon through CREB in the liver [31,43] , whereas calcium signaling cascades converge with CREB in skeletal muscle [8,44] . In addition, nitric oxide increases PGC-1 α level and increases mitochondrial biogenesis through the cGMP pathway [45,46] . On the other hand, downregulation of nitric oxide synthase 3 by TNF- α results in reduced expression of PGC-1 α and mitochondrial biogenesis in fat and muscle cells [47] . Activation of AMP-activated protein kinase also results in increased expression of PGC-1 α and a subset of PGC-1 α target genes [48] . Several other transcription factors, including MADS box transcription enhancer factor 2, ERR- α and ERR- γ , similarly increase PGC-1 α transcrip-tion in a tissue-specific manner [8,49] . In addition, PGC-1 α can be regulated through post-transcriptional modifications. p38MAPK phosphorylates PGC-1 α and increases its protein stability [50] . This phosphorylation leads to the release of inhibitory factors that bind to PGC-1 α , such as p160 MBP [51] . Moreover, PGC-1 α activity is also modulated through methylation [52] and acetylation [34,35] . Protein arginine methyltransferase 1 methylates PGC-1 α in the C-terminal region which enhances PGC-1 α transcription activity [52] . Deacetylation of PGC-1 α by SIRT1 increases the activity of PGC-1 α , which increases gluconeogenesis in the liver [35] and fatty acid oxidation and mitochondrial biogenesis in muscle [53-55] . On the other hand, acetylation of PGC-1 α by the histone acetyltransferase, GCN5, suppresses PGC-1 α activity in the liver and muscle and affects the expression of PGC-1 α target genes in glucose and lipid metabolism [34,54] . These regulators of PGC-1 α represent potential candidates for pharmaceutical intervention to increase PGC-1 α activity.

1.3.2 Dysregulation of PGC-1 a in diseases Altered PGC-1 α expression in different tissues was found to be associated with various diseases. PGC-1 α expression has been shown to be dysregulated in key metabolic tissues for glucose and fat metabolism, including adipose tissue, skeletal muscle and liver. PGC-1 α mRNA levels in skeletal muscle biopsies from T2D patients were found to be reduced in some studies [20] , but unaltered in others [56] . The expres-sion of OXOPHOS genes, targets of PGC-1 α , was also reduced in T2D patients [19,20] . Interestingly, muscle PGC-1 α expression was shown to be decreased as well in the first-degree relatives of T2D patients [20] , suggesting dysregulation of PGC-1 α expression and mitochondrial function might occur early in the development of T2D.

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In addition, PGC-1 α expression seems to decline in correlation with ageing, concomitant with reduced mitochondrial function [17,57] . Furthermore, a Gly482Ser polymorphism in the PGC-1 α gene has been associated with T2D in some populations [58-60] . In fat cells, PGC-1 α expression was found to be reduced in morbidly obese and insulin-resistant individuals [61,62] . Interestingly, treatment of obese, insulin-resistant mice with the PPAR- γ agonist rosiglitazone was shown to improve insulin sensitivity and enhance mitochondrial function in white adipose tissue [63] . In liver, PGC-1 α expression was reported to be markedly elevated in diabetic rodents, which might contribute to increased fasting blood glucose levels in these mice [31] .

The other two tissues in which PGC-1 α is expressed at a high level are the heart and brain. Cardiac PGC-1 α expression was found to be downregulated in several mouse models that display pathologic cardiac hypertrophy and heart failure [64-68] . The downregulation of PGC-1 α expression is consistent with the impairment of mitochondrial function seen in hypertrophied and failing heart [64-66] . In addition, PGC-1 α null mice develop signatures of heart failure when they are subjected to pressure overload challenges [39] . These results suggest that impaired PGC-1 α action might contribute to the development of heart failure. PGC-1 α expression was also found to be reduced in patients with Huntington ’ s disease [69,70] . Mice lacking PGC-1 α are more susceptible to oxidative stressor-induced neurodegeneration, suggesting that dysregulation of PGC-1 α expression might play a role in the development of neurodegenerative diseases [28,69,70] . Given the known function of PGC-1 α in regulating various metabolic pathways and mitochondrial function in multiple tissues, it is not surprising that its expres-sion is dysregulated in the diseases showing metabolic derangements and impaired mitochondrial function. However, whether dysregulation of PGC-1 α plays an etiologic role in these diseases remains to be determined.

2. Targeting PGC-1 a pathway for the treatment of metabolic diseases

The important role of PGC-1 α in the regulation of mitochondrial function together with the association between mitochondrial dysfunction and insulin resistance and T2D imply that activation of PGC-1 α in muscle and adipose tissue could have great potential in the prevention and treatment of metabolic disorders. Direct activation of PGC-1 α is not an attractive approach as it might not be amenable to pharmacologic intervention. Targeting the regulators of PGC-1 α is a possible alternative approach. Among these regulators, ERR- α and SIRT1 seem to be of particular interest for the development of small molecule drugs as both have been shown to be critical in mediating PGC-1 α -induced mitochondrial biogenesis and oxidative metabolism. The other two members of the PGC-1 family, PGC-1 β and PRC (PGC-1 related co-activator), also play a

role in the regulation of mitochondrial biogenesis [23] . Thus, activation of these factors might also have potential to enhance mitochondrial function.

2.1 Estrogen-related receptor a ERR- α is an immediate downstream target of PGC-1 α , as its expression is induced by PGC-1 α [26] . In addition, PGC-1 α strongly enhances ERR- α transcription activity and ERR- α was shown to play a critical role in the action of PGC-1 α on mitochondriogenesis [26,71-73] . In fact, the effect of PGC-1 α in promoting mitochondrial biogenesis requires ERR- α , as the induction of mitochondrial biogenesis by PGC-1 α in cells was largely suppressed when ERR- α expression or activity was reduced [71,73] . Moreover, ERR- α and NRF-2, together with PGC-1 α , form a positive feed-forward loop to promote mitochondrial biogenesis in muscle [26] . Furthermore, overexpression of a constitutively active ERR- α (VP16-ERR- α ) replicates many effects of PGC-1 α overexpression on mitochondriogenesis and fatty acid oxidation in cells [71,72] . Thus, activation of ERR- α with small molecules might represent an alternative strategy for the activation of PGC-1 α in order to increase mitochondriogenesis and insulin sensitivity.

A possible hurdle to the development of ERR- α activators is the size of the ligand binding pocket in ERR- α , which seems to be too small to viably accommodate compounds larger than glucose [74] . Indeed, it seems that ERR- α is a constitutively active nuclear receptor, but its binding to PGC-1 α leads to strong activation of ERR- α transcriptional activity [74] . Thus, it might be possible to develop agents that promote/facilitate the interaction of ERR- α with PGC-1 α [74] , leading to increased mitochondriogenesis in target tissues. Such agents would presumably have to bind to ERR- α at a site other than the classical ligand binding domain.

Potential side effects could be an issue with activating ERR- α , as suggested by the reported association between the level of expression of ERR- α and increased risk of recurrence and adverse clinical outcome in breast carcinoma [75,76] as well as poor cancer-specific survival rates in prostate cancer [77] . However, there is no direct evidence that activation of ERR- α will increase the risk of developing cancer.

2.2 Silent information regulator/sirtuin-1 The NAD + -dependent deacetylase SIRT1 belongs to the sirtuin family (class III histone deacetylases) and has been shown to deacetylate multiple lysine sites on PGC-1 α , thus leading to its activation [35,53-55] . Other substrates of SIRT1 include p300, p53, NCoR (nuclear receptor co-repressor), NF- κ B, and FOXO [35,78-84] . SIRT1 is the mammalian ortholog of yeast Sir2. In yeast and flies, Sir2 is an NAD + -dependent histone deacetylase that, when over-expressed, extends the lifespan of the organism [85,86] . In addition, the ability of calorie restriction (CR) to extend the lifespan in yeast and flies is abrogated when Sir2 is deleted,

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thus underscoring the importance of this protein in pathways that respond to CR [86-88] . A major function of SIRT1 seems to be promoting survival and stress resistance in times of adversity (e.g., CR) [89] . Recent evidence implicates SIRT1 in several aspects of metabolic responses and health benefits to CR, that is, glucose metabolism [35] , insulin secretion [90,91] and adipose tissue metabolism [83] . Interestingly, several single nucleotide polymorphisms in the human sirt1 gene have been found to be significantly associated with energy expenditure [55] . The levels of SIRT1 protein are increased following CR in white adipose tissue, skeletal muscle, liver, brain and kidneys [46,83,92,93] . In white adipose tissue, SIRT1 decreases adipogenesis and lipid stores, at least in part by repressing PPAR- γ activity through docking with the co-repressors NCoR and SMRT (silencing mediator of retinoid and thyroid hormone receptors) [83] . In pancreatic β -cells, SIRT1 positively regulates insulin secretion through inhibition of UCP2 expression [90,91] . Thus, activation of SIRT1, possibly independently of PGC-1 α , could improve glucose tolerance by facilitating insulin secretion, in addition to its apparent effects on insulin sensitivity [53,55] .

Activation of SIRT1 with small molecules, which triggers an increase in PGC-1 α activity in the liver, is predicted to result in an enhancement of gluconeogenesis [35] . This effect would be counterproductive in the treatment of T2D, where hepatic glucose production is inappropriately high to begin with. However, results from in vivo studies in mice suggest that the overall, systemic effects of SIRT1 activation with resveratrol are positive with regards to blood glucose homeostasis [55] and liver lipid content [53] . These data suggest that the favorable effects of SIRT1 activation on insulin sensitivity counteract its possible undesired promotion of gluconeogenesis in the liver. Activation of SIRT1 is predicted to affect the acetylation of other proteins in addition to PGC-1 α and the functional consequence of altering the acetylation of these proteins in vivo remains to be determined.

The strongest evidence that SIRT1 activation with a small molecule is possible, and that this action does have positive metabolic repercussions in vivo , was recently established with resveratrol. Resveratrol, a natural polyphenolic SIRT1 activator found in the skin of grapes, activates SIRT1 through allosteric interaction, resulting in an increase in the affinity of SIRT1 for both NAD + and the acetylated protein substrate [94] . Resveratrol has been shown recently to increase lifespan and improve the metabolic condition of mice fed on a high fat diet [53,55] . In these papers, resveratrol was shown to have a major impact on liver lipid metabolism and skeletal muscle mitochondrial content. In addition, Lagouge et al. [55] showed that in muscle cells and in embryonic fibroblasts, the effects of resveratrol on PGC-1 α acetylation, as well as on the expression of genes involved in OXOPHOS and fatty acid oxidation, are dependent on SIRT1. Thus, activation of SIRT1 represents a promising approach to treating metabolic disease, in part through an increase in PGC-1 α activity.

3. Expert opinion and conclusion

3.1 Improvement and restoration of mitochondrial capacity provides a new therapeutic approach to treat metabolic disorders T2D has become a worldwide epidemic with dire, unmet medical needs. The challenge that the pharmaceutical industry faces is to develop safe and effective therapies that positively impact the progression of this disease by improving peripheral insulin sensitivity and preserving pancreatic β -cell function. Therapies that mitigate the underlying pathogenesis of insulin resistance could, in theory, be both preventive and therapeutic to T2D. Emerging evidence from human studies strongly suggests that impaired mitochondrial function is one of the underlying pathogeneses of T2D. Exercise training, a physiologic stimulant of mitochondrial biogenesis and function, improves insulin sensitivity and glucose homeo stasis in obese, insulin resistant and diabetic patients. Moreover, improvement of mitochondrial function could increase the capacity for fatty acid oxidation and protection from reactive oxygen species accumulation, both of which have a positive effect on insulin sensitivity and glucose homeostasis [21,95] . It is worth noting that mitochondrial function was found to be impaired in insulin resistance and diabetic patients and rodents; however, whether mitochondrial dysfunction plays an etiologic role in the development of insulin resistance warrants further investigation. Nevertheless, we believe that restoration and improvement of mitochondrial function has great potential in preventing and treating obesity, insulin resistance and T2D.

3.2 Potential drug targets for enhancing mitochondrial function through PGC-1 a PGC-1 α is a master regulator of mitochondrial function and oxidative metabolism. Activation of PGC-1 α in cells and rodents strongly promotes mitochondrial biogenesis and enhances cellular oxidative capacity. Thus, PGC-1 α provides a useful node for the modulation of mitochondrial function. Proteins that modulate PGC-1 α function by affecting its transcription and/or activity represent potential targets for pharmaceutical intervention. At present, the two most well-validated targets to activate PGC-1 α are ERR- α and SIRT1. ERR- α agonists or SIRT1 activators are expected to increase PGC-1 α expression or activity, respectively, which in turn enhance mitochondrial function ( Figure 1 ).

It is worth noting that overexpression of PGC-1 α promotes hepatic gluconeogenesis in rodents. This effect in isolation would be highly undesirable in a treatment against diabetes. However, gluconeogenesis is regulated by a number of pathways and is repressed by insulin. Activation of PGC-1 α in other tissues, such as muscle and adipose tissue, will enhance insulin sensitivity, which might compensate for a possible increase in hepatic glucose production by increasing glucose use. This pattern seems to be the case with the SIRT activator resveratrol, which results in an

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increase in PGC-1 α activity in the liver, muscle and fat, and improves whole body insulin sensitivity and glucose homeostasis. Thus, it appears that activation of PGC-1 α in muscle and fat, leading to an enhancement of insulin sensiti-vity, can outweigh its possible gluconeogenic effect in the liver and result in a therapeutically positive outcome for diabetic patients.

3.3 Enhanced mitochondrial function has other therapeutic implications beyond metabolic diseases Mitochondria are dynamic organelles and serve as the center stage for oxidative metabolism, nucleotide and lipid biosynthesis, apoptosis and reactive oxygen species homeostasis. Thus, functional impairment of this organelle adversely affects many biologic processes and could contribute

to the development of diseases. Indeed, in addition to diabetes, dysregulation of mitochondrial function has been linked to neurodegeneration, cancer, cardiomyopathy and muscle wasting [96] . Although the role of mitochondrial dysfunction in the pathogenesis of human diseases remains to be elucidated, restoration/improvement of mitochondrial function through activation of PGC-1 α might have other therapeutic applications beyond diabetes ( Figure 1 ).

Acknowledgements

The authors are grateful to J Smith (Sirtris Pharmaceuticals, Inc.), SC Stevenson, T Hughes (Novartis Institutes for BioMedical Research, Inc.) and Y-S Tzeng (Boston University) for helpful comments on the manuscript.

PGC-1aEnhanced mitochondrialdensity/function

Drugs(e.g. SIRT1 activator and

ERR-α agonist)

Potential therapies formetabolic diseases and

others

Figure 1 . Drugs that, directly or indirectly, enhance PGC-1 a activity or expression should enhance mitochondrial density and/or function and provide potential treatments for metabolic diseases including obesity, insulin resistance and diabetes as well as other diseases such as neurodegeneration, cardiomyopathy and muscle wasting. ERR: Estrogen-related receptor; PGC: Peroxisome-proliferator-activated receptor-γ co-activator.

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• An review on mitochondria and human diseases.

Affi liation Zhidan Wu†1 PhD & Olivier Boss†2 PhD †Author for correspondence 1 Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, MA 02139, USA E-mail: zhidan.wu@novartis.com 2 Sirtris Pharmaceuticals, Inc., Cambridge, MA 02139, USAE-mail: oboss@sirtrispharma.com

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