Biologia.uniroma1.it

European Journal of Clinical Investigation (2005) 35, 82– 92
Peroxisome proliferator-activated receptor γ: the more
the merrier?
C. A. Argmann*, T.-A. Cock* and J. Auwerx*†
*Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch,
France; †Institut Clinique de la Souris, Génopole Strasbourg, 67404 Illkirch, France Abstract
The consequence of activating the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARγ), which coordinates adipocyte differentiation, validatesthe concept, ‘you are what you eat’. Excessive caloric intake leads to fat formation if theenergy from these nutrients is not expended. However, this evolutionary adaptation to storeenergy in fat, which can be released under the form of fatty acids, potent PPARγ agonists,has become a disadvantage in today’s affluent society as it results in numerous metabolicimbalances, collectively known as the metabolic syndrome. With the surge of human andgenetic studies on PPARγ function, the limitations to the benefits of PPARγ signalling havebeen realized. It is now evident that the most effective strategy for resetting the balance ofthis thrifty gene is through its modulation rather than full activation, with the goal to improveglucose homeostasis while preventing adipogenesis. Finally, as more PPARγ targetedpathways are revealed such as bone homeostasis, atherosclerosis and longevity, it is mostcertain that the PPARγ thrifty gene hypothesis will evolve to incorporate these.
Keywords Atherosclerosis, longevity and bone, metabolism, mouse models, PPARγ.
Eur J Clin Invest 2005; 35 (2): 82– 92
PPARγ in a westernised society
and dietary pressures for which no adaptation has beenpossible in such a short time [1]. Besides the increase in Coinciding with the modernisation of society was the emerg- availability and intake of calories, it is predicted that a number ence of the western lifestyle diseases including obesity and of crucial nutritional characteristics of our ancestral diet the metabolic diseases that are associated with it such as have been fundamentally altered during the Neolithic and hyperlipidemia; insulin resistance; type 2 diabetes mellitus industrial era including: the glycaemic load; fatty acid (T2DM) and cardiovascular disease. Because genetically, balance; macronutrient balance; trace nutrient density; our bodies are viewed as being virtually identical to what acid–base balance; sodium–potassium balance and fiber they were some 20 000 years ago, it is believed that the content [1]. Because thrifty metabolism was evolutionarily appearance of agriculture, the domestication of animals and programmed to coordinate cycles of feast or famine and the industrial revolution have created new environmental physical activity or rest (Fig. 1), discordance has now beencreated between our lifestyle, and the genes, which aresuited to them [1,2]. One gene that has been identified at Institut de Génétique et de Biologie Moléculaire et Cellulaire, the centre of this feed forward pathway that favours energy CNRS / INSERM / Université Louis Pasteur, 67404 Illkirch, France storage by adipocytes is PPARγ. As PPARγ activity is governed ( C.-A. Argmann, T.-A. Cock, J. Auwerx); Institut Clinique de la by the binding of small lipophilic ligands, mainly fatty acids Souris, Génopole Strasbourg, 67404 Illkirch, France ( J. Auwerx) derived from nutrition or meta-bolism (reviewed in [2] and Correspondence to: Johan Auwerx, The Institut de Génétique et [3]), it is not unlikely that the level of PPARγ activity has de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, F-67404 been altered throughout evolution. Because the activation Illkirch, France. Tel.: +33 388653425; fax: +33 388653201, of PPARγ leads to adipocyte differentiation and fatty acid storage, the exposure of people to prolonged chronic levels of Received 11 November 2004; accepted 30 November 2004 fatty acid-like PPARγ ligands, akin to the westernised lifestyle, PPARγ, the more the merrier? 83
Human genetic variants
PPARγ is mainly known for its role in adipogenesis, anobservation based on molecular and cellular studies thatshowed that the expression of PPARγ in cells is sufficient toinduce adipocyte differentiation [9]. Moreover, targetedmutagenesis of the PPARγ gene in embryonic stem (ES) cellsand knocking down the endogenous PPARγ2 in cell linesconfirmed the commanding role of PPARγ in adipocyte dif-ferentiation [10,11]. Consistent with this, PPARγ has beenshown to increase the expression of genes that promote fattyacid storage, whereas it repressed genes that induce lipolysisand the release of free fatty acids (FFAs) in adipocytes [2,12].
PPARγ’s role in adipogenesis in man has been underscored by human genetic association studies that tie the PPARGlocus on chromosome 3p25-p24 with obesity in Pima Indi- Figure 1 The impact of dietary input and lifestyle on peroxisome
ans [13]. More striking is that of the more than 40 different proliferator activated receptor gamma (PPARγ) activity and the reported associations of genetic variation and population balancing act of lipids and tissues in energy homeostasis. Our biochemical cycle has been evolutionarily programmed to risk to T2DM, the most widely reproduced association is coordinate cycles of feast with famine and physical exercise. One that of the Pro12Ala polymorphism in PPARγ [14,15]. The candidate gene that has been identified at the center of this feed less common alanine allele was originally reported to induce forward pathway that favours energy storage by adipocytes is an impressive 70% reduction in risk in T2DM in Finnish PPARγ. The interactions between the main metabolic tissues that and second-generation Japanese populations [16], a finding store (adipose tissue) and oxidize (skeletal muscle and liver) free subsequently confirmed in a large independent study [17].
fatty acids (FFAs) are influenced by dietary-derived FFAs and Although this association was initially challenged by four adipokines. Adipokines are subdivided into insulin sensitising (e.g. subsequent ‘negative studies’, a recent metaanalysis of all adiponectin) and insulin resistance (tumour necrosis factor α) published data involving over 25 000 cases of diabetes, has adipokines. The thickness of the arrows reflects the force of the unequivocally confirmed these data and suggests that effects. Two different conditions are compared, the response to the hunter and gatherer diet and to the western lifestyle.
patients who carry the proline allele have an odds ratio of1·27 of developing T2DM [14]. The risk allele has only amodest effect on an individual basis; however, the proline through a feed-forward pathway would result in obesity [4 – allele is very common, especially in European populations (75%) and in terms of a population-attributable risk, it isa staggering 25% [14]. The broad impact of this variant onthe risk of T2DM and its unique localization to the NH2terminus (responsible for ligand-independent transcrip- Thrifty metabolism
tional activity) (Fig. 2) makes understanding how thisvariant affects insulin sensitivity important for accelerating Obesity is more prevalent in affluent societies and so too the development of novel pharmacological agents. At the are the metabolic diseases, such as the metabolic syndrome, molecular level, the Pro12Ala polymorphism, which introduces which put a heavy social and economic burden on society.
a missense change in the coding region of the PPARγ2 gene, Strategies to lessen the disease burden include diet and exercise in vitro, is suggested to induce a partial loss of function as regimes as well as the rigorous treatment of hypertension, a result of decreased DNA-binding affinity and reduced dyslipidemia and hyperglycaemia. Ironically, the synthetic transcriptional activity [16,18](Fig. 2). Because genes do PPARγ ligands such as thiazolidinediones (TZDs), which not work in a vacuum, the potential for gene–environment increase the body’s sensitivity to insulin, have the unfortunate interaction must also be considered, especially as some find- side effect to also promote fat accretion [7,8]. The long-term ings for the Pro12Ala PPARγ variant have been reported to consequences of this are unknown. Moreover, the mecha- differ depending on the superimposition of environmental nism by which TZDs act and why they are effective is still factors, such as obesity and the ratio of unsaturated to sat- not understood. In this review we summarize the studies urated fatty acids [19,20]. The Pro12Ala PPARγ variant has that shed new light on the role of PPARγ in adipose tissue also been associated with other phenotypes such as longevity, homeostasis and emphasize that insulin sensitization can be hypertension and birth weight, which may provide further achieved without the concomitant increase in fat deposition by mechanistic insights into the mechanisms of this variant modulating PPARγ activity. In addition to obesity however, in vivo [21–23]. In addition to the Pro12Ala PPARγ variant, altered PPARγ activity through our westernised lifestyle has even more compelling evidence for a link between insulin potentially influenced bone homeostasis, atherosclerosis sensitivity and PPARγ in humans has come from studying risk and longevity, as recent literature supports their signif- individuals with dominant negative/complete loss of func- icant regulation by PPARγ. Thus, in this review we have also tion mutations occurring in the ligand-binding domain. The highlighted the role of PPARγ in nonadipose tissue.
dominant negative/loss of function mutations that have been 2005 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 35, 82– 92
together with the characterization of mice chimaeric forPPARγ–/– ES cells [11], showed the importance of PPARγin adipose tissue development in vivo. Until the past year,determination of the physiological function of PPARγin mice had been limited to studies in the heterozygousPPARγ+/– mice, which was a difficult model to comprehendas these mice are resistant to the obesity and insulin resist-ance that is induced by a high-fat diet [31,32]. To overcomethe embryonic lethality, mice with tissue-specific deletionsof PPARγ have been generated to help elucidate the tissuespecific activities of PPARγ (summarized in Table 1).
The specific reduction of PPARγ1 and PPARγ2 in the adiposetissue revealed the essential role of PPARγ in adipogenesis[33,34]. Moreover, the essential role of adipose tissue inwhole body metabolism was exemplified by the significant Figure 2 Genetic and pharmacological evidence supporting
mortality rate (> 40%) of the WAT-specific hypomorphic PPARγ’s relationship with adipogenesis and insulin sensitivity. PPARγ1 and PPARγ2 knockdown mice (PPARγ hyp/hyp), Human mutations, mouse models and pharmacological studies which were severely lipodystrophic [33]. When an aP2-driven demonstrate that the level of PPARγ activity directly corresponds Cre recombinase transgene was used to excise PPARγ1 and to adipose mass (adipogenesis). By contrast, insulin sensitivity can PPARγ2 from the mature adipocytes, a more moderate be achieved by both inhibition and activation of PPARγ, as reduction of adipose mass was observed, which was accom- illustrated by the human mutations and pharmacological studies. panied by hyperlipidemia and liver steatosis [34]. This was Pro495Leu mutation is equivalent to Pro467Leu mutation in human PPARγ1.
in contrast to the surviving adult PPARγhyp/hyp mice, whichdid not have liver steatosis or dyslipidemia [33]. Liver stea-tosis or dyslipidemia were predominantly prevented in thePPARγhyp/hyp mice by efficient oxidation of excess lipids in identified include Phe388Leu, Pro467Leu (also known as the muscle by PPARα- and PPARβ/δ-driven pathways.
Pro495Leu in PPARγ2), and Arg425Cys, which have been Intriguingly, both adipose PPARγ-deficient models had associated with partial lipodystrophy resulting in loss of relatively normal glucose tolerance [33,34]. Confirmation fat from the limbs and buttocks ([24 – 27] and reviewed in of the importance of PPARγ’s role in maintaining the integ- [15]), severe insulin resistance, diabetes and hypertension rity and function of the mature adipocyte has been recently [28]. Although these studies provide direct genetic evidence shown through the selective ablation of total PPARγ in of a link between PPARγ action and the regulation of mam- adipocytes of adult mice [35]. PPARγ-deficient mature malian glucose homeostasis, it remains uncertain whether adipocytes die within a few days, but are replaced days later the profound effects on insulin resistance observed in these with newly differentiated PPARγ-expressing adipocytes.
individuals is only a manifestation of reduced adipose tissue Thus PPARγ is essential for the in vivo survival of mature mass or whether other direct effects of PPARγ action on adipocytes and hence PPARγ antagonists are potentially insulin signalling are impaired. In contrast to the individuals usefully to reduce obesity acutely [35]. The PPARγ gene with loss of function mutations, a rare Pro115Gln substitu- encodes two isoforms that are generated by the use of alternate tion renders PPARγ constitutively active and carriers of this promoters and differential splicing sites [36,37]. PPARγ2 mutation are obese but remain insulin sensitive [29]. PPARγ has an additional 30 amino acids in its NH terminal, which activity in humans corresponds directly to adipose mass, and is thought to be why PPARγ2 is more effective in gene acti- not necessarily with insulin sensitivity (Fig. 2), suggesting vation compared to PPARγ1 [38]. Until recently, the relative that only part of PPARγ’s effects on glucose homeostasis is contribution of the two PPARγ isoforms for adipogenesis dependent on white adipose tissue (WAT).
in vivo remained unknown, but in vitro studies suggest thatPPARγ2 is better suited to adipogenesis [39,40]. Studies inmice selectively disrupted in adipose PPARγ2 expression Mouse genetic variants
demonstrated reduced levels of adipose tissue, specificallyWAT and were insulin insensitive [41]. The lack of a com- Genetic manipulations of PPARγ in the mouse began with plete absence of fat indicates that PPARγ1 alone is able to the generation of a PPARγ–/– mouse using conventional gene drive the development of adipose tissue but that PPARγ2 targeting strategies. Unfortunately, these mice die in utero plays the dominant role in adipogenesis. The presence of resulting from major placental and cardiac defects and impaired insulin sensitivity in the face of normal glucose although a PPARγ–/– animal could be rescued by tetraploid tolerance in these mice was hypothesized to be a conse- aggregation, this mouse died within days as a result of severe quence of reduced levels of plasma leptin and adiponectin lipodystrophy [30]. The lipodystrophy in this PPARγ–/– mouse 2005 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 35, 82– 92
PPARγ, the more the merrier? 85
Table 1 A comparison of the main PPARγ tissue specific knockout mice models
The different mouse models have various age and diet-dependent responses, thus for simplicity the above descriptions are for the adult phenotype in the postprandial state on a chow diet, at the age indicated.
Abbreviations: N/D (not determined), TG (triglcyerides), FFA (free fatty acids), apoE (apolipoprotein E), LDL (low density lipoprotein).
insulin-sensitizing effects of TZDs on muscle are indirect PPARγ in the liver and muscle and that muscle PPARγ is not involved in insulin sensing Although PPARγ is predominantly expressed in the adipo- [44]. These findings are consistent with the observations in cyte, both the skeletal muscle and the liver express small the PPARγhyp/hyp mouse model that shows adipose tissue but significant levels of PPARγ and furthermore, are tissues PPARγ expression is crucial for the insulin-sensitizing effects that are important in glucose and fuel homeostasis. There- of TZDs, as TZD treatment of these mice only ameliorated fore, tissue-specific knockout models were created to define glucose intolerance but not insulin resistance [33]. In con- PPARγ’s function in the muscle and liver. Consistent with trast to Norris et al., Hevener et al. reported that mice lack- the adipose tissue-specific PPARγ knockout models, lipid ing PPARγ specifically in the muscle develop severe muscle balance was also significantly altered when either muscle or insulin resistance and as a result are hyperinsulinemic, liver PPARγ was obliterated. Deletion of PPARγ in the livers of glucose intolerant and hypertriglyceridemic. Because TZD two mouse models with significant steatosis (leptin-deficient treatment of these mice did not augment the insulin- ob/ob or lipodystrophic A-ZIP/ F-1 mice) reduced the liver stimulated glucose disposal by the muscle the authors con- triglyceride content, although it elevated serum FFAs cluded that TZD treatment did not enhance muscle insulin and lipoproteins and induced insulin resistance, illustrating sensitivity and therefore muscle PPARγ is a direct target of PPARγ’s role in liver lipogenesis [42,43]. Because in the TZDs [45]. Most studies however, suggest that PPARγ in absence of WAT, the ability of TZD (thiazolidinedione) the muscle is more responsible for coordinating the use of treatment to lower triglycerides and glucose was dependent energy rather than directly controlling glucose homeostasis on liver PPARγ, the general consensus is that in the absence or responses to insulin [33,34,42 – 44], validating the con- of WAT, liver PPARγ participates in both fat regulation and cept that WAT is predominantly responsible for the insulin- glucose homeostasis [42] but in the presence of WAT, the sensitizing effects of PPARγ. PPARγ in the WAT therefore, impact of PPARγ in the liver on glucose homeostasis is may not only be the master regulator of adipogenesis in vivo minimal. The role of PPARγ in the muscle is much less obvi- but also a driving force of glucose and lipid homeostasis.
ous in light of two independent reports of muscle-specific The above mouse models have helped us to realize that PPARγ knockout mouse models, which are essentially oppo- when PPARγ is absent in any of the three tissues, whole-body site [44,45]. Norris et al. report that muscle-specific PPARγ lipid homeostasis and insulin sensitivity are significantly knockout mice have normal glucose homeostasis and insulin altered. This is a fascinating observation considering that levels but have reduced hepatic insulin sensitivity, suggested PPARγ expression levels vary greatly among these tissues to be a consequence of the increased WAT mass. The inef- with adipose tissue having the highest PPARγ expression ficient use of lipid as fuel by the muscle explained the shunt levels and the liver and muscle very little. The resulting of lipid to the adipocyte and the enhanced adiposity. As dis- repartitioning of lipids that occurs in these mouse models ruption of muscle PPARγ did not block the beneficial effects has also unveiled the presence of a complex network of cross of TZDs on glucose homeostasis, it was concluded that the talk between the liver, adipose and muscle that is essential 2005 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 35, 82– 92
in order to maintain energy balance. This balance is in part type 2 diabetic patients (reviewed in [55] and [56]). TZDs achieved by the adaptation of PPARγ in the nontargeted increase WAT mass, redistribute it from visceral to sub- tissues and by the other PPAR isoforms, PPARα and β/δ, cutaneous deposits and induce the appearance of small, which enhance fatty acid oxidation to minimize hyperlipi- newly differentiated adipocytes (reviewed in [57]). TZDs, daemia and the consequential insulin resistance.
furthermore have an impact on the production of FFAs andthe secretion of several adipokines such as TNFα, leptin,resistin, and adiponectin and can also via this way, affect PPARγ in other mouse tissues insulin signalling in other tissues (reviewed in [58]). Exciting In contrast to adipose tissue, muscle or liver, the deletion of is the development of a new class of high-affinity tyrosine-based PPARγ in the pancreas did not result in a metabolic phenotype, receptor agonists, exemplified by farglitazar, that acts by but it underscored the antiproliferative role of PPARγ [46].
releasing the corepressor, silencing mediator of retinoic acid In comparison to adipocyte PPARγ, macrophage PPARγ and thyroid hormone receptors (SMRT) from PPARγ [59].
has a similar function in that it regulates lipid homeostatic These SMRT releasers are extremely potent and efficacious genes including LPL and CD36. In macrophage-specific PPARγ agonists that can even promote wild-type levels PPARγ deficient mice lipid homeostasis in the arterial wall of transcriptional activation by the PPARγ mutants Val290Met was significantly impaired and the development of athero- and Pro467Leu mutants, both of which respond poorly to classical TZD treatment [59]. These data underscore theimportance of corepressor release in attaining nuclear receptortranscriptional responses [59,60].
Human PPARγ mutations in the mouse Whereas potent and efficacious PPARγ activation is invari- The knowledge obtained from the tissue specific deletions of ably associated with increased fat mass, PPARγ antagonism PPARγ is further refined by the generation of mouse models is neutral or even reverses weight gain. This principle was carrying specific PPARγ mutations such as the knock-in illustrated by the binding of the partial agonist FMOC-L- of alanine at position 112 (S112A). This mutation, which Leu to PPARγ, which induces the differential recruitment renders PPARγ constitutively active (like the human Pro115Gln of coregulators to PPARγ such that glucose levels are still mutation) preserves insulin sensitivity during diet-induced lowered but there is no weight gain [54]. Alternatively, the obesity [49] as a result of smaller fat cells, elevated serum partial PPARγ agonists, such as NC-2100 [61] or MCC- adiponectin and reduced FFA levels. Thus the phosphor- 555 [62], also show little effect on adipocyte differentiation, ylation state of PPARγ modulates insulin sensitivity suggesting but have remarkable antidiabetic activities. Partial inhibition that compounds designed to modulate PPARγ phosphor- of either PPARγ or its heterodimerization partner the retin- ylation may selectively enhance insulin sensitivity without oid X receptor (RXR) by antagonists [63 – 65] also improved increasing weight gain. Another mouse model that expresses insulin sensitivity, consistent with human and mouse genetic the analogue of a human dominant negative PPARγ muta- studies. Whether there are PPARγ-independent effects of tion, Pro467Leu [50] tackled the dogma that hypertension TZDs which can account for some of these differences is is a consequence of the insulin resistance in the wake of currently under intense investigation [7,66,67].
PPARγ deficiency and lipodystrophy [51]. The PPARγ Collectively, the mouse models of ablated PPARγ expres- Pro467Leu mice develop severe hypertension despite mild sion in metabolic tissues, the human mutational analysis fat redistribution and minimal insulin resistance. This and these pharmacological studies demonstrate that PPARγ uncoupling between lipodystrophy, insulin resistance and activity corresponds directly to adiposity in a linear fashion hypertension, implies direct modulation of blood pressure (Fig. 2A). However, unlike PPARγ’s relationship with fat mass, by PPARγ possibly through regulating the renin angiotensin PPARγ activity is not linearly related to insulin sensitivity, system activity in adipose tissue [50,51]. This hypothesis as inactivation and activation of PPARγ can both enhance supports the decrease in blood pressure observed with TZD insulin sensitivity (Fig. 2B). This nonlinear relationship indi- treatment and emphasizes the continued value of using cates that insulin sensitivity is an integrated effect achieved natural mutations to understand receptor function and predominantly by modulating PPARγ actions within the adipose tissue with effects on adipokine secretion and lipidstorage in addition to other tissue-specific PPARγ responses,as revealed by tissue-specific PPARγ obliterated models.
Pharmacological studies
PPARγ binds multiple ligands that can modulate its activityand induce a full spectrum of receptor activities from full PPARγ and bone homeostasis
inhibition (antagonist) to activation (agonist) (Fig. 2). PPARligands have been generated with varying degrees of effects In terms of a PPARγ-driven thrifty gene response, physical which can be attributed to their ability to either differentially activity and food procurement are inextricably linked in that recruit cofactors [54] or to selectively activate or inactivate physical activity is required to obtain food before the energy PPARγ tissue-specific manner (SPPARMS). Full PPARγ in the food can be used or stored. Thus, it is plausible that agonists, such as the first generation TZDs, improve insulin concomitant with PPARγ’s role in securing a constant sup- sensitivity, glucose tolerance, and the lipidemic profile in ply of substrate to fuel muscle contraction and brain activity, 2005 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 35, 82– 92
PPARγ, the more the merrier? 87
it also regulates bone mass to provide the physical strength and gelatinase B (MMP-9) by a DNA binding-independent required in procuring the next meal. PPARγ’s influence on mechanism involving negative interference with the trans- osteogenesis and bone homeostasis was first suggested cription factors AP-1, NF-κB and STAT-1. Furthermore, by the single silent nucleotide mutation polymorphism of PPARγ ligands inhibited the phorbol ester-induced produc- PPARγ that was associated with lower bone mineral density tion of proinflammatory cytokines, TNFα, IL-1 and Il-1α [68] and higher leptin levels [69]. Studies using natural and [78]. These inhibitory effects would be expected to be bene- synthetic PPARγ agonists [70,71] also demonstrated adverse ficial in the context of atherosclerosis, however, it was orig- effects on bone formation in mice. Whether these effects inally uncertain whether the 15d-PGJ - and TZD-mediated reflected PPARγ-dependent or PPARγ-independent effects inhibition of the synthesis of these pro-inflammatory genes of these PPARγ agonists remained, however, elusive until was a PPARγ-dependent effect [74]. Studies in PPARγ-null heterozygous PPARγ-deficient mice were reported to have macrophages demonstrated that contrary to the initial enhanced bone mass as a result of increased osteoblasto- beliefs, PPARγ is neither essential for macrophage differ- genesis [72]. But which PPARγ-expressing tissue contributed entiation or for mature macrophage functions such as to enhanced bone formation? This question was answered pro-inflammatory cytokine production [79,80].
in the severely lipodystrophic PPARγhyp/hyp mouse model, In addition to the inflammatory responses mediated which do not express PPARγ1 and PPARγ2 in WAT [73].
by PPARγ ligands they may also influence atherosclerosis The specific absence of PPARγ in fat robustly increased through regulating macrophage lipid and lipoprotein bone mass as it favoured mesenchymal stromal precursor metabolism. Macrophage uptake of atherogenic lipoproteins cells to undergo osteogenic differentiation rather than adipo- within the arterial wall results in cholesteryl ester deposition genic differentiation. The absence of PPARγ in adipocytes and foam cell formation, which are hallmarks of early and also limited their capacity to secrete antiosteogenic-signalling late atherosclerosis. PPARγ targets both lipoprotein uptake factors, including leptin, further enhancing the bone and cholesterol efflux, two competing processes involved in phenotype [73]. In addition, the strongly enhanced bone macrophage lipid homeostasis. PPARγ activation induces mass consequentially reduced the bone marrow cavity and expression of the scavenger receptor CD36, thereby pro- hematopoiesis. Bone marrow hematopoiesis was compen- moting oxidised low density lipoprotein (oxLDL) uptake sated for by extramedullary hematopoiesis in the spleen and formation of foam cell. In addition to the acquisition [73]. If these data obtained in the mouse models can be of cholesterol, however, macrophage uptake of oxLDL extrapolated to humans, inhibition of PPARγ activity could provides the cell with naturally occurring PPARγ ligands, be an interesting strategy to combat osteoporosis. It also thereby promoting further PPARγ activation and CD36 up- warrants careful following of T2DM patients treated regulation. Such a feed-forward cycle predicts that PPARγ with PPARγ agonists to detect eventual development of is predominantly pro-atherogenic [75,81]. However, subse- quent studies in mice treated with PPARγ or RXR ligandsdemonstrated reduced atherosclerosis [82 – 85]. This anom-aly was resolved when PPARγ activation was shown to pro-mote the removal of cholesterol from macrophages through PPARγ and atherosclerosis
enhancing the cholesterol efflux mediated by the ATP-bindingcassette transporter A1 (ABCA1). This stimulates HDL In addition to the above thrifty activities of PPARγ in WAT, formation (high-density lipoprotein) and reverse cholesterol PPARγ activity in alternate cells such as macrophages might transport. The expression of the ABCA1 is tightly regulated by also be beneficial from an evolutionary perspective as it cellular cholesterol content through the oxysterol-dependent could favour the innate immune response [74]. As PPARγ activation of another nuclear receptor, the liver X receptor is also expressed in endothelial and smooth muscle cells (LXR). PPARγ has been shown to activate ABCA1 expres- there has been a push to understand the role of PPARγ in sion indirectly via enhanced transcription of LXR [47,83] the vasculature, in order to unravel the complex pathophysi- and possibly through coupled up-regulation of LXR ligand ologic alterations that relate insulin resistance and metabolic production; as PPARγ has been recently demonstrated to perturbations to tissue injury in the blood vessel leading to up-regulate CYP27 expression and consequently the pro- atherosclerosis. An important outstanding question is duction of the oxysterol, 27-hydroxycholesterol [86]. PPARγ whether PPARγ influences the risk of myocardial infarction and LXR cooperate to modulate other lipid regulating genes. Conditional disruption of PPARγ in mice in addition One way PPARγ may influence cardiovascular disease to lowering the expression of ABCA1 and ABCG1 also development is through modulating arterial macrophage lowered the expression of apoE, CD36, LXRα and LPL inflammation, lipid and lipoprotein metabolism. PPARγ genes [48]. Given that both of these nuclear receptors are is expressed in monocytes and up-regulated during their activated by lipid components of oxLDL, PPARγ and LXR differentiation into macrophages [75]. In fact, the extent of actually comprise a cascade that coordinates a response to macrophage differentiation or activation has been linked to oxLDL uptake [87]. Whether this response is pro or antia- the extent of PPARγ expression [76]. PPARγ ligands oppose therogenic will depend on their net effect on cellular processes several events that occur during macrophage activation.
mediating lipid uptake, cholesterol efflux and inflammation.
Ricote et al. [77] demonstrated that natural and synthetic These data emphasize the potential involvement of PPARγ ligands inhibited IFNγ-induced expression of iNOS PPARγ in the pathogenesis of atherosclerosis, which was 2005 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 35, 82– 92
underscored in humans by the association of the PPARγPro12Ala polymorphism with a protection from coronaryheart disease [88] and more recently with reduced carotidintimal medial thickness [89]. The efficacy of PPARγ ago-nists to reduce atherosclerosis in mice [82,83] and to exertvasculo-protective effects in humans [90 – 93] are attributedto both its effects on inflammation and cholesterol effluxthat can be receptor-dependent and receptor-independent[66,67,79,80]. Further studies are required to define howmuch of these effects are the result of PPARγ’s beneficial sys-temic metabolic effects vs. its vascular and immune effects,which themselves might be indirect and mediated via LXR.
It is also interesting to speculate that the increased frequencyof atherosclerosis could be a PPARγ-driven maladaptedmacrophage response, which occurs when the inherentbeneficial effects (stimulation of the innate immune responseand cholesterol efflux) are overwhelmed by the pro- Figure 3 Energy metabolism and longevity compared under
atherogenic effects (increased oxLDL uptake). Such condi- conditions of caloric excess and caloric restriction. Compared to tions are probably created by the chronic overload of lipids caloric excess, caloric restriction decreases energy levels leading to that is associated with our current affluent lifestyle.
activation of a signalling cascade to enhance longevity. Decreased glucose intake by the cell reduces the flow of carbon through the glycolytic pathway and thus decreases glycolytic-derived NADH and the conversion of ADP to ATP. Signalling by the insulin / PPARγ and longevity
insulin-like growth factor 1 (IGF-1) is attenuated under these conditions, which allows for forkhead transcription factor (FOXO)- From an evolutionary perspective, the thrifty response induced stress resistance, cell cycle arrest and apoptosis (antiaging). Sirtuin 1 (Sirt1), a NAD+-regulated chromatin deacetylase, clearly favours survival when food supply is limited. Caloric prolongs lifespan in response to caloric restriction in lower restriction, meaning a diet that is low in calories without organisms. Sirt1 mediates these effects by deacetylating FOXO3 undernutrition has, however, also been shown to extend and /or FOXO4, thus attenuating FOXO-induced apoptosis but mammalian lifespan [94 – 96] (Fig. 3). The beneficial effects potentiating FOXO-induced cell-cycle arrest [106 –108]. Extremes of caloric restriction are associated with altered metabolism, in fat mass are inversely related to lifespan, and PPARγ has recently particularly reduced metabolic rate and oxidative stress, been implicated in influencing longevity. Sirt1 may modulate decreased fat mass, body temperature and fasting glucose PPARγ target genes and ultimately influence energy expenditure in addition to improved insulin sensitivity and altered and fat storage. Dotted lines represent hypothesized effects and the neuroendocrine and sympathetic nervous system (reviewed in size of arrow or words corresponds to the importance of the effect.
[97]). One major genetic pathway identified to regulate thelifespan of Caenorhabditis elegans, which is highly conservedamong vertebrates and invertebrates is the insulin and / or FOXO [104]. Caloric restriction increases Sirt1 expression insulin-like growth factor-1 (IGF-1) signalling pathway in several tissues in the rat including the brain, liver, kidney (IIS) (reviewed in [98]). Reduced signalling through the IIS and visceral fat pads, a response attenuated in the presence pathway by mutations in Daf-2, the insulin receptor homo- of insulin or IGF-1 [105]. Sirt1 may modulate longevity in logue in C. elegans, can extend lifespan and this response relies mammals by tipping the balance from cell death towards on the presence of the C. elegans homologue of the forkhead cell survival. Sirt1 achieves this effect by regulating the transcription factors, Daf-16 (FOXO1-3 in mammals) activity of at least three classes of mammalian damage ([99] and reviewed in [100]). FOXO transcription factors responsive factors. First, Sirt1 deacetylates the p53 protein play a key role in transmitting insulin signalling downstream at lysine 382, thereby inactivating p53-mediated transcrip- of protein kinase B, which inhibits FOXO activity through tion and apoptosis. Second, Sirt1 deacetylates the DNA phosphorylation and nuclear exclusion (Fig. 3). However, repair factor Ku70, causing it to sequester the proapoptotic under activating conditions (as seen in cases of decreased factor Bax away from mitochondria, thereby inhibiting stress- IIS) FOXO proteins move to the nucleus and regulate genes induced apoptotic cell death; and finally Sirt1 deacetylates involved in glucose metabolism, cell cycle regulation, FOXO3 and /or FOXO4, thus attenuating FOXO-induced apoptosis and oxidative stress responses. The ultimate apoptosis but potentiating FOXO-induced cell-cycle arrest consequence being increased stress resistance, a major hall- mark of caloric restriction [101 – 103].
Adipose tissue is consistently implicated as a critical tissue A second longevity regulatory gene is the evolutionarily in mediating extension of lifespan by altering the IIS path- conserved NAD+-regulated histone deacetylase silent way as demonstrated by the extended lifespan in the fat information regulator (Sir2) (human orthologue Sirt1).
specific insulin receptor knockout mice [99]. This is in line Sirt1 promotes survival in yeast, C. elegans and mammals with two recent observations showing that limited expression in response to food scarcity and this requires the presence of of the FOXO proteins in the Drosophilia fat body and brain 2005 Blackwell Publishing Ltd, European Journal of Clinical Investigation, 35, 82– 92
PPARγ, the more the merrier? 89
or its overexpression in the Drosophilia fat body is sufficient to uncontrolled cell proliferation and cancers. However, these mediate its effects on life span [109,110]. However, repres- adaptations in the context of our current affluent lifestyles sion of adipogenesis and fat retention in relation to caloric that afford excessive exposure to natural PPARγ ligands, restriction was also recently explained by the inhibition throw this once tightly regulated system into a metabolic of PPARγ. Sirt1 was demonstrated to repress PPARγ and turmoil causing the so-called metabolic syndrome. This hence activation of fat storage genes, by docking to the metabolic syndrome encompasses all of today’s most prev- PPARγ corepressor NCoR and SMRT [111]. In Sirt1+/– alent diseases including obesity, T2D, and atherosclerosis.
mice, mobilization of fatty acids from white adipocytes upon Collectively our current knowledge suggests that modulating fasting was compromised, supporting Sirt1 and PPARγ (or inhibiting) PPARγ activity, rather than activating it, will be inactivation as the molecular pathway connecting caloric the preferred therapeutic strategy to treat metabolic disorders, restriction to life extension in mammals [111]. Consistent as this will improve glucose homeostasis, yet prevent with this mouse model is the fact that the hypomorphic human Pro12Ala genetic variation in PPARγ was reportedto be associated with increased longevity [21]. Thus PPARγmay represent another longevity regulatory gene.
Two major outstanding questions include how caloric Acknowledgements
restriction stimulates Sirt1 activity and whether a caloricrestriction mimetic can be developed as a prolongevity strat- This work was supported by grants from CNRS, INSERM, egy. With respect to the first dilemma, two hypotheses have Hopitaux Universitaires de Strasbourg, EU, EMBO and been proposed to explain caloric restriction and Sirt1 acti- NIH. We thank the members of the Auwerx Laboratory for vation: 1) by depleting nicotinamide, an inhibitory product of Sirt1 itself or 2) by increasing the NAD+/ NADH ratio.
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