Transcriptional coregulators in the control of energy homeostasis

Review

TRENDS in Cell Biology

Vol.17 No.6

Transcriptional coregulators in the control of energy homeostasis Je´roˆme N. Feige1 and Johan Auwerx1,2 1 2

Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire, CNRS/INSERM/Universite´ Louis Pasteur, 67404 Illkirch, France Institut Clinique de la Souris, 67404 Illkirch, France

Metabolic programs controlling energy homeostasis are governed at the transcriptional level by the integrated action of several transcription factors. Among these, nuclear receptors including peroxisome proliferator-activated receptors, estrogen-related receptors or thyroid hormone receptors play prominent roles by adapting gene expression programs to the endocrine and metabolic context that they sense via their ligand-binding domain. Coregulators assist nuclear receptors to positively or negatively influence the transcription of target genes, and thereby comprise an integral part of the transcriptional circuitry. This review focuses on how coregulators, including PGC-1 and p160 coactivators, Sirt-1, RIP140 and NCoR corepressors, control the balance between energy storage and expenditure, with a particular emphasis on how these proteins integrate physiological stimuli in vivo. The general picture that emerges indicates that these coregulators are metabolic switches, which convergently regulate metabolic pathways through their pleiotropic interactions with nuclear receptors and other transcription factors. Introduction Transcriptional regulation is vital for homeostasis and enables the adaptation of physiological processes to external cues [1]. The transcriptional control of metabolism is conserved from simple prokaryotes to complex eukaryotes such as humans. In eukaryotes, nuclear receptors (NRs; see Glossary) and several other transcription factors are key players that integrate signals from dietary, metabolic and endocrine pathways to control target gene expression ([2,3] and Box 1). This enables them to coordinate metabolic processes by adapting tissue responses to various challenges and by tuning interorgan communication through the integration of both endogenous and exogenous signals. NRs themselves confer a first level of specificity to these mechanisms in space and time through their tissuespecific expression patterns, their specific binding to target gene promoters, and through the tuning of their activity via post-translational modifications and ligand binding. Transcription factors, however, do not function alone and require coregulators to modify and epigenetically remodel chromatin structure and to bridge the complexes in which they reside to the basal transcriptional machinery. These coregulators, which can both have positive Corresponding author: Auwerx, J. ([email protected]). Available online 1 May 2007. www.sciencedirect.com

(coactivator) and negative (corepressor) actions on target gene transcription [4–6], thus confer a second level of specificity to the transcriptional response (Figure 1). The activity of coregulators is, in turn, regulated through the spatial and temporal control of their expression and activity in response to metabolic cues. Furthermore, transcriptional coregulators constitute a huge reservoir of interacting partners, comprising more than 200 proteins. This diversity allows them to establish specific yet interdependent

Glossary and abbreviations ACTR: activator of thyroid and retinoic acid receptors ADP: adenosine diphosphate AIB: amplified in breast cancer-protein AMP: adenosine monophosphate ATP: adenosine triphosphate BAF: BRG1/BRM associated factor BAT: brown adipose tissue BRG1: Brahma-related gene 1 BRM: Brahma cAMP: cyclic AMP CBP: CREB binding protein C/EBP: CCAAT/enhancer binding protein CREB: cAMP-responsive element binding protein DRIP: vitamin D receptor interacting protein ETC: electron transport chain ERR: estrogen-related receptor FAD: flavin adenine dinucleotide FOXO: forkhead box protein O GAPDH: glyceraldehyde-3-phosphate dehydrogenase GCN5: general control of amino acid synthesis protein 5 GRIP: glucocorticoid receptor interacting protein HNF: hepatocyte nuclear factor LDH: lactate dehydrogenase LXR: liver X receptor MAPK: mitogen-activated protein kinase Med: mediator MEF: mouse embryonic fibroblast MEF2D: myocyte-specific enhancer factor 2D NAD: nicotinamide adenine dinucleotide NCoEx: nuclear corepressor exchange factors NCoR: nuclear receptor corepressor NR: nuclear receptor TCA: tricarboxylic acid cycle Adiponectin: an adipokine, i.e. a protein secreted by the adipose tissue. Upon binding to its specific membrane receptors AdipoR1 and 2, adiponectin promotes AMP kinase and PPARa signaling and thereby promotes fatty acid oxidation [36]. In addition, adiponectin enhances insulin sensitivity by stimulating glucose uptake in skeletal muscle and by inhibiting hepatic gluconeogenesis. Lipodystrophy: a disease characterized by the absence of fat, either caused by the abnormal development or by the degeneration of the adipose tissue.

0962-8924/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2007.04.001

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Box 1. Transcriptional control of energy homeostasis Energy homeostasis, i.e. the balanced regulation between energy intake, storage and expenditure, is under the tight control of several transcription factors, including many nuclear receptors (NRs) [2,3]. Transcription factors playing a major role in energy homeostasis include the NRs peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs) and thyroid hormone receptors (TRs), as well as other non-NR transcription factors, such as the nuclear respiratory factors (NRFs), the CCAAT/element binding proteins (C/EBPs) and the sterol regulatory element binding protein (SREBP). PPARa and PPARb/d promote fatty acid oxidation in the liver and the muscle. ERRa also controls muscular fatty acid catabolism in addition to its action on mitochondria, where it cooperates with NRFs to promote mitochondrial DNA replication and oxidative phosphorylation. TRs participate in the regulation of fatty acid oxidation and cooperate with PPARs and ERR to control thermogenesis in the brown adipose tissue. By contrast, PPARg and C/EBPs regulate energy storage by controlling adipocyte differentiation and fat storage in the adipose tissue; SREBP regulates lipogenesis.

interaction networks that determine the specificity of the transcriptional complexes. Metabolic homeostasis requires a tight regulation of the equilibrium between energy intake, storage and expenditure (Figure 1). The mechanisms controlling energy intake involve both the control of nutrient uptake in the gut and the regulation of appetite, which is controlled centrally and involves a hormonal communication between the brain and peripheral tissues such as the gastrointestinal tract

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and the adipose tissue [7]. Despite recent progress in the identification of peptides controlling appetite, and of their downstream signaling pathways, the potential cross-talk with transcriptional coregulators remains unexplored. By contrast, the implication of coregulators in regulatory nodes controlling energy storage and expenditure has grown exponentially in the past few years. This review therefore focuses on these two aspects of energy homeostasis. Given the potential value of new preventive and therapeutic applications to target metabolic disorders by modulating coregulator activity, we highlight recent work that emphasizes the importance of post-translational modifications to determine coregulator action. Coregulators and the regulation of energy storage In higher eukaryotes, energy can be stored as carbohydrates or as lipids. Carbohydrates, which are stored as glycogen in muscle and the liver, can be rapidly mobilized in response to high energy demands, such as those occurring during exercise or fasting. Lipids, stored as triglycerides in the adipose tissue, constitute a long-term energy reservoir. To our knowledge, the implication of NR coregulators in glycogen synthesis and degradation has not been described. Coregulators, however, were shown to play a crucial role in controlling fat accretion, mostly ascribed to the modulation of the activity of the peroxisome proliferator-activated receptor g (PPARg), the master regulator of adipocyte differentiation and lipid storage [8–10].

Figure 1. Coregulators affect metabolic equilibriums by conferring a second level of specificity to the transcriptional response. They do this by modulating the activity of transcription factors (depicted in blue). They thereby influence physiological processes (depicted in orange), regulating the metabolic equilibrium between energy storage and expenditure. However, their implication in energy intake remains unexplored. A feedback exists between the two levels of specificity and transcription factors can regulate the expression of coregulators. www.sciencedirect.com

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PPARg corepressors as anti-adipogenic molecules Corepressors such as NCoR and SMRT (also called NCoR-2) associate with NRs in the absence of ligand to repress their transcriptional activity. The physiological relevance of their implication in metabolic regulations has been demonstrated in the context of PPARg-mediated adipogenesis, during which they promote a target-genespecific repression of PPARg activity [11]. A negative action of SMRT and NCoR on fat storage has been suggested by the enhanced adipogenesis and increased expression of proadipogenic PPARg target genes after RNAi-mediated inhibition of these corepressors [12]. These cellular observations have, however, not yet been extended to the in vivo situation because of the embryonic lethality of knockout mouse models [13]. The NAD+-dependent deacetylase Sirt1 also limits adipogenesis by inhibiting PPARg activity through the formation of a corepressor complex that also includes NCoR and SMRT [14]. Sirt1 activation will thus trigger lipolysis and loss of fat, whereas reduced Sirt1 activity limits the mobilization of fatty acids. Other corepressors with distinct molecular actions also repress PPARg activity. The transcriptional coactivator with the PDZ-binding motif (TAZ) is a ligand-independent PPARg corepressor that inhibits adipogenesis but promotes osteoblast differentiation through coactivation of Runx2 [15]. Given the common embryonic origins of adipocytes and osteoblasts, TAZ could therefore represent an important switch that determines mesenchymal cell fate. The scaffold attachment factor B1 (SAF-B1), which represses PPARg and whose expression is downregulated during adipogenesis, potentially represents a novel class of coregulators that regulate transcription by linking NRs to the nuclear architecture [16]. The unphosphorylated retinoblastoma protein, RB, is also a PPARg corepressor. It inhibits the clonal expansion phase of adipocyte differentiation by recruiting the histone deacetylase 3, a protein mediating transcriptional inhibition through histone tail deacetylation [17]. RB and related pocket proteins, such as p107, are, however, also required for terminal adipocyte differentiation because of their effects on CCAAT/enhancer binding protein (C/EBP) signaling [18,19]. Furthermore, pocket proteins inhibit genetic programs controlling the differentiation of brown fat [18,19]. Finally, it is noteworthy that certain corepressors interact with NRs only in the presence of ligand [20]; the implication of such corepressors in adipogenesis has not yet been characterized. PPARg coactivators exert pro-adipogenic actions Upon ligand binding, corepressor/coactivator exchange is achieved by ligand-dependent changes in the affinity of coregulators for the receptor and also through the proteasomal degradation of corepressors. Corepressor exchange factors (NCoEx), such as transducin b-like 1 (TBL1) and the related protein TBLR1, are specialized coregulators that promote corepressor degradation by acting as adaptors to recruit the ubiquitylation machinery [21]. The inability of TBL1 / embryonic stem cells to differentiate into adipocytes demonstrates that NCoEx are essential to PPARg signaling [22]. Active corepressor removal thus seems important for fat accretion. www.sciencedirect.com

The SWI/SNF complex, which controls ATP-dependent chromatin remodeling, also influences the differentiation of adipocytes. The expression of a dominant negative BRG1 or BRM ATPase blocks adipogenesis and inhibits the expression of PPARg2 by suppressing the recruitment of general transcription factors and RNA polymerase II at the PPARg promoter [23]. Whereas SWI/SNF ATPases are required for PPARg-mediated action on adipogenesis, the anchoring of the SWI/SNF complex to PPARg, which occurs through BRG1/BRM-associated factors (BAFs), probably involves redundant interactions, because BAF60c does not influence adipocyte differentiation despite interacting with and coactivating PPARg [24]. CBP and p300 are two homologous coactivators with histone acetyltransferase activity. They were initially identified as coactivators of the cAMP-response element binding protein (CREB) and they coactivate a multitude of transcription factors. Heterozygous CBP-deficient mice are strongly lipodystrophic because white adipose tissue (WAT) is undeveloped, but the integrity of other organs seems unaffected [25]. In addition, CBP+/ mutant mice are resistant to diet-induced obesity. The cell-autonomous adipogenic actions of CBP were furthermore demonstrated by the impaired capacity of CBP+/ mouse embryonic fibroblasts (MEFs) to differentiate into adipocytes, an effect resulting both from the inhibition of the positive actions of PPARg and C/EBPb on adipocyte differentiation and from the inhibition of SREBP-mediated lipogenesis [25]. In addition, the related coactivator p300 is required for adipocyte differentiation [26]. Interestingly, CBP+/ mice are insulin sensitized [25] despite their lipodystrophy, a phenomenon usually associated with insulin resistance. This apparent contradiction is perhaps related to the role of CBP in gluconeogenesis [27]. In fact, insulin-induced phosphorylation of CBP in a site close to the CREB-binding domain participates in the suppression of gluconeogenesis upon feeding. Conversely, upon fasting, CREB phosphorylated after glucagon-dependent cAMP activation, can recruit CBP to stimulate gluconeogenesis. The absence of CBP could hence impede gluconeogenesis and result in insulin sensitization, thereby revealing that coactivation by CBP has a negative output on metabolic regulations. The mediator complex is a large, multiprotein complex of coactivators that bridges transcription factors to the basal transcriptional machinery. The subunit 1 of this complex (Med1, also called TRAP220, DRIP205 and PBP) plays an important role in adipocyte differentiation by coactivating PPARg; as Med1 / MEFs have lost their adipogenic potential [28]. However, because Med1 bridges NRs to the mediator complex and is indispensable for NRmediated transcription, the absence of Med1 can affect many NR-mediated regulations. A liver-specific Med1 inactivation consistently inhibits hepatic PPARa signaling [29], suggesting that Med1 could also be implicated in energy expenditure by promoting PPARa-mediated oxidation of fatty acids. By contrast, non-NR transcription factors do not seem to rely on Med1 to contact the mediator complex and MyoD-stimulated myogenesis is normal in Med1 / fibroblasts [28]. The invalidation of the steroid receptor coactivator 2 (SRC-2 or TIF2/GRIP1) in mice results in a lean phenotype

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that correlates with the decreased expression of genes involved in the uptake and storage of fatty acids and with increased lipolysis [30]. In addition, the expression of genes required for fatty acid synthesis, such as fatty acid synthase, were decreased in the liver of SRC-2 / mice [31]. Together with the induction of SRC-2 in WAT upon high-fat feeding, and the positive actions of SRC-2 on adipocyte differentiation [30,32], these results demonstrate that SRC-2 exerts positive effects on fat storage, at least in part by coactivating PPARg. The related coactivator SRC-3 (also known as p/ CIP, AIB-1 and ACTR) also plays an important role in fat storage: It is enriched in the adipose tissue and its inactivation results in decreased adiposity and smaller adipocytes, even in mice fed regular chow [32]. The absence of SRC-3 totally abolishes adipocyte differentiation by altering PPARg-dependent transcription of genes that are important for lipid storage and by inhibiting the capacity of C/EBP a and d to induce the adipose tissue-specific PPARg2 isoform. It was suggested that SRC-1, the third member of the p160 family, cooperates with SRC-3 because double SRC-1/SRC-3 knockout mice are also lean [33]. However, the absence of a metabolic phenotype in the SRC-1 / and SRC-3 / mice in this study strongly contrasts with two reports demonstrating that SRC-1 / and SRC-3 / mice are, respectively, fatter and leaner than their wild-type littermates [30,32].

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Although this discrepancy could be linked to differences in the experimental models, it is likely that invalidation of the SRC-3 gene primarily accounts for the lean phenotype of the double SRC-1/SRC-3 mutant animals. New PPARg coactivators with adipogenic actions are emerging, with molecular functions that extend beyond chromatin remodeling and histone modifications. For example, the PPARg-interacting protein PRIP acts as a molecular scaffold that cooperatively enhances PPARgand RXR-mediated transcription [34]. The coactivator PRIP is a positive regulator of adipogenesis and is recruited to the aP2 promoter in adipocytes. Consistent with this observation, PRIP / MEFs fail to sustain PPARg-mediated adipogenesis [35]. Coregulators and the regulation of energy expenditure Although the effect of coregulators on energy storage can contribute to whole-body energy homeostasis, abnormalities in energy expenditure are often the major determinants of metabolic disorders. The global impact of coregulators on whole-body energy homeostasis depends on their capacity to modulate the metabolic balance by promoting or inhibiting anabolic and catabolic functions (Figure 2). Whereas WAT is the main organ implicated in

Figure 2. The role of coregulators in the balance between energy storage and energy expenditure. Energy homeostasis is maintained through the integrated action of various factors and signals, which control the metabolic balance by influencing antagonist actions in distinct organs. Obesity is characterized by an excess of fat, which accumulates through the activation of adipogenesis in WAT and through the inhibition of energy expenditure in energy-consuming tissues such as the muscle, the BAT and the liver. Conversely, leanness results from the inhibition of adipogenesis and the promotion of energy expenditure. In this figure, we represent the actions of coregulators in this two-dimensional control of energy homeostasis. www.sciencedirect.com

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Table 1. Organ-specific functions of coregulators in the control of energy homeostasisa Energy storage

SRC-2 SRC-3 CBP Med1 NCoRs

Energy expenditure

WAT Adipogenesis (+ via PPARg) Adipogenesis (+ via PPARg) Adipogenesis (+ via PPARg) Adipogenesis ( via PPARg)

PGCs

SRC-1

RIP140

Thermogenesis ( via PPARs, ERR, TR?) Oxidative phosphorylation ( via ERR?) Fatty acid oxidation ( via PPARs, ERR?)

BAT Thermogenesis ( via unknown targets) Mitochondrial uncoupling ( )

Muscle

Fatty acid oxidation ( )

Liver Fatty acid oxidation (+ via PPARs?) Fatty acid oxidation ( ) Fatty acid oxidation (+ via PPARa)

Mitochondrial biogenesis and oxidative phosphorylation (+ via NRFs, ERRs) Thermogenesis (+ via PPARs, ERR, TR) Thermogenesis (+ via PPARs, ERR, TR)

Mitochondrial biogenesis and oxidative phosphorylation (+ via NRFs, ERRs) Fatty acid oxidation (+ via PPARs, ERRa)

Gluconeogenesis (+ via HNF-4, FOXO1, GR) Fatty acid oxidation (+ via PPARs, ERRa)

Thermogenesis ( via PPARs, ERR, TR)

a The functions of major coregulators in metabolic tissues are given. The transcription factors demonstrated or presumed to mediate these effects, as well as their activation (+) or inhibition ( ) of these biological programs, are also mentioned. Empty cells indicate that the functions are unknown.

the regulation of energy storage by coregulators (see previous section), the brown adipose tissue (BAT), the muscle and the liver constitute the main sites of energy expenditure (Table 1). CBP and SRC-2, prototypes of coregulators acting on the two sides of the energetic balance to promote fat accretion As well as their positive action on adipocyte differentiation, which we outlined above, CBP and SRC-2 exacerbate fat storage by inhibiting energy expenditure. The lean phenotype of CBP+/ and SRC-2 / mice results from a major imbalance in energy homeostasis (Figure 2). PPARa and PPARa target genes controlling fatty acid oxidation and energy uncoupling are induced in the muscle, liver and BAT of CBP+/ mice [25]. The fact that CBP+/ animals have increased adiponectin levels further testifies to a catabolic state [36]. It is therefore clear that CBP inhibits energy expenditure by reducing fatty acid oxidation, although the molecular pathway controlling this effect remains to be uncovered. The protection from obesity observed in SRC2 / animals is linked to enhanced adaptive thermogenesis in BAT [30] and mitochondrial function in skeletal muscle (Coste and Auwerx, unpublished results), through an upregulation of the expression of PGC-1a and of its downstream oxidative targets (see later and Box 2). However, the molecular basis of these repressive actions of SRC-2 on energy expenditure is also unknown. Finally, the similarity in the lean phenotype of SRC-2 and SRC-3 mutant mice [30,32] and the structural conservation between these coactivators indicate that the implication of SRC-3 in energy expenditure merits further study. RIP140, a corepressor acting as a negative regulator of energy expenditure RIP140 is a ligand-dependent corepressor that interacts with a multitude of ligand-activated and orphan NRs to www.sciencedirect.com

control important metabolic functions [37]. RIP140 / mice are leaner than their control littermates, even when challenged by high-fat feeding [38]. Interestingly, this phenotype is not linked to a defect in adipogenesis and

Box 2. Oxidative phosphorylation and mitochondrial biogenesis Mitochondria are the cellular powerhouses that provide cells with most of their energy under the form of ATP through oxidative metabolism. The degradation of glucose and fatty acids produces acetylCoA, which can rapidly shuttle through the TCA cycle to generate ATP and the reduced equivalents NADH and FADH2, which, in turn, can yield more ATP through oxidative phosphorylation. In this process, NADH and FADH2 are oxidized by a series of proteic complexes known as the electron transport chain (ETC). These utilize oxygen and electron transport to generate a chemical gradient of protons across the inner mitochondrial membrane. This proton gradient is subsequently converted to ATP by phosphorylation of ADP by the ATP synthetase. Alternatively, the proton gradient can be uncoupled from ATP synthesis by uncoupling proteins, which generate heat and protect against excessive oxidative stress generated by electron leakage. Oxidative phosphorylation is particularly important for fatty acid catabolism, which generates high levels of reduced equivalents. When fatty acids are the most abundant energy substrate (during endurance exercise, for example), the level of oxidative phosphorylation can be tuned by regulating the expression of the proteins forming the ETC complexes and by increasing the number/content of mitochondria through mitochondrial biogenesis. ETC proteins are encoded both by nuclear and mitochondrial genes. In the nucleus, their expression is regulated by the nuclear respiratory factors (NRFs) and the estrogen-related receptor a (ERRa), whereas the mitochondrial ETC genes are regulated by the transcription factor Tfam, which is encoded in the nucleus and directly regulated by NRF-1 [45]. Tfam also controls mitochondrial DNA replication and maintenance, thereby implicating this factor, as well as its upstream regulator NRF-1, in mitochondrial biogenesis. Defects in mitochondrial functions have been associated with metabolic disorders [46,70,71] and increasing oxidative phosphorylation has therefore been proposed as a strategy to limit the deleterious effects of highfat feeding.

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RIP140 / cells retain both the capacity to differentiate into adipocytes [38] and to express normal levels of adipogenic markers, such as aP2 and PPARg [39]. However, the WAT of these animals expresses high levels of UCP-1 [38], a protein normally confined to the BAT, where it contributes to adaptive thermogenesis (Box 2). This effect on UCP1 expression is due to a direct inhibition of the UCP-1 promoter by RIP140 [39]. In addition to repressing the uncoupling of respiration, RIP140 inhibits other aspects of energy expenditure in the adipose tissue by repressing genes implicated in fatty acid oxidation, mitochondrial biogenesis and oxidative phosphorylation, resulting in increased mitochondrial density in adipocytes lacking RIP140 [40]. Given the high expression levels of this coregulator in WAT [38], and its induction during adipogenesis [41], it seems reasonable to speculate that RIP140 acts as an inhibitor of energy expenditure in WAT by blocking mitochondrial function in a tissue specialized in fat storage. However, the physiological validation of these results in vivo is still awaited. Interestingly, RIP140 also reduces glucose uptake in adipocytes, most probably explaining the enhanced glucose tolerance in RIP140 knockout mice [40]. Despite all these data pinpointing a metabolic function for RIP140, the nature of the NRs and transcription factors repressed by this coregulator remains an open question. The fact that the negative actions of RIP140 on glucose uptake and mitochondrial gene expression require ERRa in cellular models already indicates one effector of the action of RIP140 [40], but other receptors, such as PPARa, PPARb/d and thyroid hormone receptors (TRs), could also be involved. PGC-1s: pleiotropic regulators of energy expenditure The PPARg coactivator-1a (PGC-1a), initially identified as a PPARg interacting protein in BAT [42], is the founding member of a family of three related proteins that control major metabolic functions through the coactivation of NRs and other transcription factors [43,44]. Whereas the PGC-1related coactivator (PRC) is expressed ubiquitously, the expression of PGC-1a and PGC-1b is enriched in mitochondria-rich tissues such as BAT and cardiac and skeletal muscles, where PGC-1 family members cooperate to control mitochondrial functions such as oxidative phosphorylation and mitochondrial biogenesis ([45] and Box 2). PGC-1a function has been associated with the regulation of large clusters of genes controlling oxidative phosphorylation and mitochondrial activity [46,47]. PGC-1a-mediated mitochondrial control requires the nuclear respiratory factor (NRF) [47,48] and ERRa [49,50], transcription factors controlling mitochondrial DNA synthesis and replication, as well as the expression of many subunits of the respiratory chain ([45] and Box 2). Interestingly, this regulatory ERRa/NRF/PGC1a node constitutes an amplification loop as both transcription factors are coactivated by PGC-1a and their expression levels are auto- and interdependently induced in a PGC1a-dependent manner [48,49]. Enhanced mitochondrial function results in increased radical oxygen species (ROS) production through electron leakage in the electron transport chain. To counterbalance the elevated ROS production subsequent to the PGC-1-dependent increase in mitochondrial respiration, PGC-1a positively regulates www.sciencedirect.com

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the expression of several ROS detoxifying enzymes, such as the superoxide dismutase SOD2 and the glutathione peroxidase GPx1, thereby preventing ROS-induced deleterious effects [51]. In addition, PGC-1a also induces fatty acid oxidation by coactivating PPARa [52,53] and hepatic gluconeogenesis by stimulating the activity of the hepatocyte nuclear factor 4a (HNF-4a) and of the forkhead box protein O 1 (FOXO-1) [44]. Fasting-induced gluconeogenesis involves the cooperation of PGC-1a with CREB and its coactivator TORC (transducer of regulated CREB activity), which directly activate the PGC-1a promoter [54–56]. PGC1s have therefore emerged as major metabolic nodal points, essentially because their expression and their activity are extremely sensitive to various (patho-) physiological stimuli. In BAT, an organ specialized in heat generation, PGC-1a expression, induced by cold exposure, regulates thermogenesis by promoting mitochondrial respiration and by uncoupling electron transfer from ATP synthesis through the induction of UCP-1 [42,57–59]. Interestingly, energy expenditure in cultured brown adipocytes relies on cooperation between PGC-1a and PGC-1b [58]. Despite the increased basal thermogenesis in PGC-1b knockout animals, which results from a strong upregulation of PGC-1a, PGC-1b influences thermogenesis in vivo under conditions of norepinephrine stimulation [60]. The actions of PGC-1s on oxidative metabolism are also prominent in skeletal muscle, where PGC-1a is highly expressed in slow-twitch type I fibers that preferentially rely on fatty acids as a source of energy [61] (Box 3). The implication of PGC-1a in the contractile activity of the muscle is further illustrated by the induction of its expression by exercise [62]. When ectopically expressed in skeletal muscle, PGC-1a and PGC-1b can both drive a switch from glycolytic to oxidative fibers by coactivating the MEF2D transcription factor [61,63]. PGC-1a has the more pronounced action because it can promote the formation of several types of oxidative fiber, ranging from slow-twitch highly oxidative type I fibers to type IIa and IIx fibers, with faster contractile properties, whereas the

Box 3. Metabolic and contractile classification of muscle fibers Skeletal muscle fibers differ in their organization and metabolism to fulfill specialized mechanical movements adapted to the duration and strength of their contraction. Their classification thus relies on these two interdependent parameters. Fiber type per se is defined by the contractile phenotype, which is itself characterized by the predominant expression of myosin heavy chains. Type I fibers contract with slow twitch and are resistant to fatigue, whereas different types of type II fiber have faster contraction properties and therefore higher strength, with increasing contraction speed ranked IIa < IIx < IIb. In addition, muscle fiber classification is also based on the energetic preference of the muscle. Slow-twitch fibers can sustain long-term endurance exercise as a result of their mitochondria-rich composition, which favors oxidative metabolism and directs the fuel preference towards fatty acids. By contrast, fasttwitch fibers preferentially rely on anaerobic glucose utilization through glycolysis to meet with the intense energetic needs of rapid contraction. The contractile and metabolic classifications therefore overlap to a large extent because oxidative metabolism and contractile power are inversely correlated.

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action of PGC-1b seems restricted to the formation of type IIX fibers [63]. However, the implication of PGC-1a in fiber-type switching under physiological conditions has been challenged by the normal fiber-type composition of muscles from PGC-1a / mice [64]. This absence of a fibertype switch could potentially be linked to a compensation induced by the hyperactivity of PGC-1a / mice, because repeated exercise is known to promote oxidative fiber formation. These results suggest that PGC-1a might regulate the mitochondrial functions required for oxidative metabolism in type I fibers, rather than the composition of the fiber type per se. Although mitochondrial biogenesis does occur in PGC-1a / mice, these animals consistently exhibit impaired oxidative phosphorylation in the skeletal muscle [64], most probably causing the altered exercise performance observed under forced exercise [59]. In addition, PGC-1a also controls mitochondrial activity in the heart, where this role helps to ensure efficient cardiac contraction [52,64], and in the central nervous system, where PGC-1a-driven energy homeostasis is indispensable to sustain neuronal function [51]. PGC-1b and PRC participate with PGC-1a to a common regulatory network that controls energy expenditure by promoting oxidative phosphorylation [45,65,66]. Furthermore, PGC-1b exerts a specific action on lipid metabolism. In the liver, PGC-1b orchestrates a lipogenic response, which is driven by its specific interaction with SREBP, through a domain that is not present in PGC-1a or PRC [67]. In addition, PGC-1b also increases circulating triglycerides and VLDL cholesterol levels, possibly through the activation of liver X receptors (LXRs), a class of NRs that sense and regulate cholesterol levels [68]. Altered mitochondrial function is a hallmark of many diseases [69], and the prominent role of PGC-1 coactivators in mitochondria implicates them in the pathophysiology of several metabolic and neurodegenerative disorders. The expression of PGC-1a and PGC-1b is decreased in skeletal muscle from diabetic subjects, thereby contributing to impaired oxidative phosphorylation [46,47]. As mitochondrial dysfunctions have been proposed as a cause of insulin resistance in human skeletal muscle [70,71], it is likely that the PGC-1s are instrumental in maintaining insulin action and that their deregulation could lead to metabolic disorders. Furthermore, because ROS have been implicated in the etiology of insulin resistance [72], the actions of PGC1a on ROS protection [51] could cooperate with its role in the control of oxidative phosphorylation to protect against diabetes. In addition, mitochondrial dysfunction and oxidative stress are strongly implicated in the pathogenesis of several neurodegenerative disorders [69]. Consistent with this observation, Huntington’s disease can result, at least in part, from reduced PGC-1a activity through direct interaction of mutated huntingtin with the PGC-1a promoter or with PGC-1a itself [73,74]. Moreover, PGC-1a / mice are more sensitive to chemically induced neurodegeneration of the substantia nigra and hippocampus, at least in part because of impaired ROS scavenging by PGC-1a [51]. It is therefore plausible that abnormal PGC-1a activity could contribute to other neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, and studies in this direction should be encouraged. www.sciencedirect.com

Tuning PGC-1 activity through post-translational modifications On top of the induction of PGC-1a expression by various metabolic stimuli, such as fasting, exercise or cold exposure, the actions of PGC-1a and related coactivators on metabolism are also controlled by post-translational modifications. Such modifications are of major importance because they link intracellular signaling pathways to transcriptional regulation. For example, PGC-1a phosphorylation is most likely involved in translating the effect of cytokine stimulation to oxidative metabolism through p38 MAP-kinase-mediated phosphorylation of PGC-1a, which enhances its activity [75,76]. In addition, methylation by the protein arginine methyltransferase 1 (PRMT1) can also enhance PGC-1a activity [77], although the physiological importance of this regulation remains to be determined. The most prominent PGC-1a post-translational modification in terms of control of its activity and of its physiological output is acetylation. Indeed, PGC-1a activity was shown to be inhibited by acetylation and the PGC-1a acetylation status is directly regulated by the balanced action of the GCN5 acetyltransferase and the NAD+-dependent Sirt1 deacetylase [78,79]. GCN5 was reported to inhibit PGC-1a-dependent hepatic gluconeogenesis whereas Sirt1-mediated PGC-1a deacetylation and activation promote glucose production in hepatocytes. Interestingly, mice treated with the natural Sirt-1 activator, resveratrol, have enhanced exercise endurance and are resistant to cold because the Sirt1-mediated PGC-1a deacetylation stimulates mitochondrial function in muscle and brown adipose tissue ([80] and Figure 3). Resveratrol also induces deacetylation of PGC-1a and phosphorylation of the AMP kinase in the liver [81], an action known to promote fatty acid oxidation and to inhibit lipogenesis. All together, this multiorgan response protects resveratrol-treated mice from diet-induced obesity by shifting the energy balance towards energy consumption rather than storage [80]. In addition, insulin sensitivity is enhanced by this energy redistribution [80]. Interestingly, resveratrol treatment also enhances longevity in mice [81], an action consistent with the implication of Sirt1 homologs in mediating the effects of caloric restriction on lifespan extension in lower eukaryotes [82]. The Sirt-1–PGC-1a connection therefore provides a means of linking the energy status of a cell, sensed by Sirt-1 through the NAD+/NADH ratio [82], to a transcriptional output on metabolic networks regulated by PGC-1a. The possibility of targeting Sirt1, by natural or synthetic agonists, and thereby coaffecting PGC-1 signaling, opens this regulatory axis to nutraceutical and pharmacological intervention to target metabolic disorders. The future of coregulators Coregulators are clearly emerging as predominant players in metabolism, which, beyond the control of ‘metabolic’ gene expression by transcription factors, provide a second, more global, level of transcriptional ‘metabolic adaptation’ (Figure 1). An extensive body of work already implicates the PGC-1 coactivators as being central to many metabolic regulatory networks. Furthermore, the implication of other coactivators in energy homeostasis is also becoming

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Figure 3. Resveratrol promotes mitochondrial functions through Sirt-1-mediated deacetylation of PGC-1a Resveratrol is a natural polyphenol found in red grapes. It can activate the Sirt-1 NAD+-dependent deacetylase through an allosteric interaction, which increases Sirt-1 affinity for both NAD+ and the acetylated substrate. Sirt-1 activation by resveratrol leads to PGC-1a deacetylation in the skeletal muscle and in the BAT, thereby promoting the mitochondrial functions regulated by PGC-1a [80]. These mitochondrial actions improve resistance to cold and to fatigue during exercise. In addition, the stimulation of energy expenditure resulting both from enhanced mitochondrial functions and from AMP kinase phosphorylation in the liver also protects against diet-induced obesity and insulin resistance [80,81].

more and more evident. Whereas all these studies addressed the role of coregulators in energy storage and expenditure, very little is known about how coregulators contribute to the control of energy intake and absorption. Interestingly, not only do coregulators regulate metabolism through their transcriptional actions but, conversely, metabolic intermediates also seem to have wide-ranging transcriptional effects by mechanisms that extend beyond the induction of coregulator expression by metabolic cues. For example, the glycolytic enzymes glyceraldehyde-3phosphate dehydrogenase (GAPDH) and lactate dehydrogenase (LDH) have been identified in an Oct-1 coactivator complex controlling the expression of the histone 2B promoter during S-phase [83]. Also, coregulator regulation through acetylation is linked to the availability of metabolic intermediates, such as acetylCoA, which acts as an acetyl donor for the acetyltransferases CBP, p300, GCN5 or SRCs, and NAD+, which is indispensable to the deacetylase activity of sirtuins. Research that combines molecular, cellular and pharmacological approaches with tissue-specific loss and gain of function in metabolic organs should enable us to uncover how coregulators orchestrate transcriptional control of metabolic networks. Another goal of metabolic research on coregulators should be to understand the contribution of different NRs and other transcription factors to the physiological actions of coregulators. This last line of investigation will be of particular importance with respect to the development of selective NR modulators as therapeutic agents in the treatment of metabolic disorders [84]. Towards that goal, the possibility of identifying receptor-specific coactivator mutants [85] could be coupled to the generation of mouse models bearing mutations that specifically abolish the interactions with a given NR. In view of the growing implication of coregulators in metabolic regulation and diseases, targeting regulatory www.sciencedirect.com

nodes under coregulator control should become a reality in the not too distant future. To date, PGC-1a is clearly the prime candidate to achieve this goal and it is possible to foresee pharmacological interventions that target both its expression (e.g. through multiple intracellular signaling pathways such as the CREB/TORC pathway [55]), and its activity (e.g. through its acetylation status regulated by Sirt-1 [80,81] and GCN5 [78]). We are, however, hopeful that other coregulators will join the list of potential metabolic targets in the near future. Acknowledgements We thank members of the Auwerx laboratory for stimulating discussions. Work in the authors’ laboratory was supported by grants from CNRS, INSERM, ULP, Hoˆpital Universitaire de Strasbourg, FRM, AFM, EU and NIH. J.N.F. is supported by a FEBS fellowship.

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