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and Its Therapeutic Modulation
Departments of Medicine (M.G., D.B.S., V.K.K.C., S.O.) and Clinical Biochemistry (D.B.S., S.O.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom
Address all correspondence and requests for reprints to: Prof. V. K. K. Chatterjee, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: kkc1{at}mole.bio.cam.ac.uk; or Prof. S. O’Rahilly, Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: sorahill{at}hgmp.mrc.ac.uk.
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Abstract |
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 Top Abstract IntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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, and a large body of in vitro and in vivo data has evolved to support their increasing clinical use. Importantly, clinical and laboratory findings in human subjects harboring natural mutations and polymorphisms within the receptor have provided additional insights. Here, we focus on the consequences of inherited variation in the human peroxisome proliferator-activated receptor gene, linking this receptor to disordered glucose homeostasis, adipogenesis, lipid metabolism, and blood pressure regulation. These studies provide further support for the future development of more selective receptor modulators, targeting specific pathways to ameliorate facets of the metabolic syndrome. |
Introduction |
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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The metabolic syndrome |
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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), and there is increasing recognition that central obesity is a key etiological factor in the development of the underlying insulin resistance (6).
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PPAR: a nuclear receptor
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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, the third member of a subset of nuclear receptors, which also includes PPAR
and PPAR
, is now recognized to be central to this process (7). The term PPAR stems from the original observation that a structurally diverse array of compounds, which activate PPAR, the first member of the subfamily to be cloned, also increases the size and number of peroxisomes in rodent liver (8). The fibrate class of hypolipidemic drugs act via PPAR, which is highly expressed in liver, kidney, heart, and skeletal muscle, but reassuringly do not promote peroxisome proliferation in humans (9, 10). Little is currently known about the physiological role(s) of PPAR, which is expressed in many tissues (11), although recent studies suggest that it may be an important regulator of cholesterol trafficking in macrophages (12, 13). In contrast, in the decade since it was first isolated (14), an extensive body of knowledge has evolved relating to the biology of PPAR. Differential promoter usage coupled with alternate splicing of the PPAR gene gives rise to three mRNA isoforms: PPAR1 and PPAR3, which encode the same protein product; and PPAR2, which contains an additional 28 amino acids at its amino-terminus. PPAR1 exhibits widespread expression, albeit at low levels, and PPAR2 and PPAR3 are highly expressed in adipose tissue (15).
Like other nuclear receptors, PPAR has a modular structure consisting of distinct functional domains (Fig. 1A). Many of its biological effects are mediated by receptor regulation of target gene transcription in a ligand-dependent manner. Following binding to specific DNA response elements (usually located in the target gene promoter) as a heterodimer with retinoid X receptor (RXR), binding of a cognate or exogenous ligand(s) induces coactivator recruitment, which in turn modulates transcription. The identity(ies) of the endogenous ligand(s) for PPAR remains a matter of debate (hence its classification as an orphan receptor), although several naturally occurring compounds, including polyunsaturated fatty acids (e.g. linoleic acid, arachidonic acid), 15-deoxy 
12, 14 prostaglandin J2 and eicosanoids [e.g. hydroxyoctadecadienoic acid (HODE) and hydroxyeicosatetraenoic acid] (16, 17, 18) have been shown to activate the receptor at concentrations comparable to physiological levels.
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gene (Fig. 1A
) in association with distinct clinical phenotypes, providing unique insights into the physiological roles of this receptor. Here, we review the key observations derived from the study of these genetic variants, to provide a broad picture of PPAR function in relation to human adipogenesis, insulin sensitization, lipid metabolism, blood pressure regulation, and atherosclerosis and, perhaps, providing justification for this nuclear receptor remaining a key therapeutic target for the continuing development of agents to treat the human metabolic syndrome. |
PPAR and adipogenesis
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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is first and foremost a master regulator of adipogenesis (19, 20). It is highly abundant in adipose tissue (11), with expression being induced early in preadipocyte differentiation (21). Studies modulating PPAR expression or action in rodent cell lines have confirmed that the receptor is both essential and, in the presence of PPAR agonists, sufficient for adipogenesis (20, 22). Although knocking out the murine PPAR gene results in embryonic lethality because of a combination of placental and cardiac defects (23, 24), fusion of mutant and normal embryonic cells has enabled selective rescue of the placental pathology thereby permitting the birth of a single live born runt, which exhibited no discernible adipose tissue (23). Furthermore, heterozygous PPAR null mice have reduced adipose tissue depots (25). So how do human studies corroborate and extend these observations?
As in rodents, human PPAR (and in particular the 2 isoform) is highly expressed in adipose tissue (26), and exposure of cultured primary human preadipocytes to PPAR agonists (e.g. thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone) induces their differentiation (27). Moreover, prior transduction of these cells with an adenovirus expressing a potent dominant-negative mutant PPAR has been shown to block this process (28). Treatment with TZDs promotes weight gain in humans and, although some have suggested this to be a consequence of improved insulin sensitivity, it is possible that lowering circulating insulin levels per se actually diminishes its anabolic activity. An alternative and more plausible hypothesis is that PPAR agonists improve insulin sensitivity by promoting adipogenesis and postprandial fatty acid/triglyceride storage within adipocytes, both of which are likely to increase adipose tissue mass. Several studies have shown that the increase in body weight associated with TZD treatment is mediated principally by accumulation of sc fat (reviewed in Ref. 29), whereas visceral adipose tissue volume is reduced or unchanged. These observations are in keeping with ex vivo studies in which preadipocytes isolated from sc abdominal adipose tissue differentiated more readily in response to TZDs than cells from visceral depots of the same subjects (27, 30).
It is not known whether TZD treatment increases sc fat mass in all body regions; this question is of particular interest because there is increasing evidence to suggest that there are important functional metabolic differences between upper body (abdominal) and lower body (including femorogluteal) sc fat (31). Selective loss of limb and gluteal fat is observed in subjects with loss-of-function mutations within the ligand-binding domain (LBD) of human PPAR (see below). In animal studies, PPAR agonists alter adipose tissue morphology dramatically with apoptosis of old, hypertrophic adipocytes and differentiation of smaller insulin-sensitive adipocytes (24), but whether TZD treatment in humans induces adipocyte hypertrophy and/or hyperplasia remains unresolved.
Recently three groups have independently identified loss-of-function mutations in the LBD of human PPAR (32, 33, 34). Together these reports describe eight adult subjects, all of whom exhibit a stereotyped form of partial lipodystrophy (Fig. 1, B and C), in which sc fat is lost from the limbs and gluteal region but preserved in both the sc and visceral abdominal depots (35, 36). Some phenotypic differences were observed with facial adipose tissue, which was reported to be normal in those subjects harboring the Pro467Leu and Val290Met mutations, reduced in the single individual with the Arg425Cys mutation and increased in the Phe388Leu kindred. Although these findings are broadly in keeping with the notion of PPAR as a key regulator of adipogenesis, it is more difficult to reconcile the pattern of selective partial lipodystrophy observed with current knowledge about adipose tissue PPAR expression and the adipogenic response to receptor agonists in humans.
With loss-of-function mutations resulting in lipodystrophy and PPAR agonists promoting adipogenesis, gain-of-function PPAR mutations might be anticipated to increase body fat mass. This does indeed appear to be the case with Ristow et al. (37) describing four morbidly obese [body mass index (BMI) 37.9 to 47.2 kg/m2] German subjects with a gain-of-function mutation (Pro115Gln) in the N-terminal domain of PPAR2. The transcriptional activity of PPAR is known to be inhibited by phosphorylation of a serine residue at codon 114 (38, 39), and the Pro115Gln mutation interferes with phosphorylation of Ser114, resulting in a receptor with constitutive transcriptional function and enhanced adipogenic activity when expressed retrovirally in NIH 3T3 fibroblasts (37).
The receptor mutations described hitherto are rare, having been identified in only a few individuals. In contrast, by far the most prevalent human PPAR genetic variant reported to date is a polymorphism, replacing alanine for proline at codon 12 (Pro12Ala) in the unique PPAR2 amino-terminal domain, with an allelic frequency that approaches 15% in some Caucasian populations (40, 41). Unlike PPAR1, which is ubiquitously expressed at relatively low levels, the 2 isoform is almost exclusively expressed in adipose tissue. Furthermore, adipose tissue mRNA levels of PPAR2 are increased in morbidly obese individuals, whereas expression of PPAR1 is reduced (30), and isoform specific knockout studies suggest that PPAR2 is the critical isoform-mediating adipogenesis (42). In some functional assays, the Pro12Ala variant exhibits reduced binding to DNA and modest impairment in transcriptional activation, and these functional properties have been correlated with the association of this polymorphism with reduced BMI, although subsequent studies have failed to confirm this finding (41, 43).
Taken together, these genetic observations support the notion that PPAR is a critical regulator of human adipose tissue mass.
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PPAR and insulin sensitivity
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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, which is closely linked to determination of fat mass, should also be involved in regulating insulin sensitivity. Studies of TZDs, a novel class of agent developed for the treatment of T2DM, have provided critical evidence to support this contention. Although synthesized originally as potentially hypolipidemic derivatives of clofibrate, the TZDs were shown unexpectedly to lower blood glucose via insulin-sensitizing actions in rodent models of T2DM and later in man (44). In the mid-1990s, Lehmann et al. (45) made the key observation that TZDs are selective high affinity ligands for PPAR, with the rank order of their potency for receptor activation in vitro correlating closely with their glucose lowering activity in vivo (46, 47).
The initial wave of enthusiasm, which accompanied the introduction of these novel agents into clinical practice, was tempered by the withdrawal of troglitazone, the first TZD in widespread use, on the grounds of hepatotoxicity (48); subsequent studies have suggested that this potentially fatal idiosyncratic adverse event is unlikely to be a class effect but rather reflects the generation of a toxic metabolite unique to troglitazone (7). Close surveillance for hepatic dysfunction following the introduction of rosiglitazone and pioglitazone has provided added reassurance, but other potentially troublesome side effects have been reported (49). More recently, selective non-TZD PPAR ligands (e.g. tyrosine agonists) have been developed and shown to exert potent antidiabetic effects in preclinical studies and early clinical trials (7, 50). Compounds that activate RXR (the heterodimeric partner for PPAR) also improve in vivo insulin sensitivity in rodent animal models (51).
Studies of human PPAR genetic variants have proved complementary to this body of pharmacological evidence, lending support to the contention that this nuclear receptor is a critical regulator of insulin action in man. For example, severe insulin resistance (with or without overt T2DM) has proved to be a remarkably consistent finding in subjects with loss-of-function PPAR mutations (Refs. 32, 33, 34 ; Gurnell, M., and D. Savage, unpublished observations) (Fig. 1D), with insulin resistance being evident even in early childhood in affected individuals (36). Detailed metabolic studies of these subjects have begun to elucidate mechanisms whereby PPAR dysfunction might lead to insulin resistance (36), augmenting and extending observations derived from in vitro work and animal studies (52). For example, both partial and generalized lipodystrophy have consistently been found to be associated with insulin resistance in animals and man (53), and it is, therefore, likely that the dramatic diminution in peripheral limb and gluteal fat found in individuals with PPAR mutations contributes to their insulin-resistant phenotype. In addition, our data suggest that even the residual adipose tissue depots in these individuals are dysfunctional, perhaps resulting in exposure of skeletal muscle and liver to unregulated fatty acid fluxes and thereby impairing insulin action in these sites (36).
Adipose tissue is also an important source of hormones, collectively referred to as adipokines, e.g. leptin (54), adiponectin (55), TNF (56), and resistin (57), many of which appear to be capable of exerting profound effects on insulin-mediated glucose disposal. For example, circulating adiponectin levels have previously been shown to correlate closely with insulin sensitivity and inversely with fat mass (58, 59, 60). TZDs increase adiponectin gene expression, suggesting that this adipokine may represent a critical link between PPAR activation and insulin sensitization (61). In support of this hypothesis, circulating adiponectin levels were found to be dramatically lower in three individuals harboring loss-of-function PPAR mutations, compared with healthy controls or subjects with non-PPAR-mediated severe insulin resistance, suggesting a direct correlation between PPAR activity and adiponectin expression (62). Further studies should help to determine the extent to which this and other adipokines contribute to the insulin-sensitizing effects of PPAR agonists.
Although the markedly deleterious loss-of-function mutations have provided unique insights into the role of this receptor in human glucose homeostasis, with profound phenotypic effects in affected individuals, they are relatively rare and make negligible genetic contribution to the risk of insulin resistance or T2DM in the general population. In contrast, the Pro12Ala polymorphism in PPAR2, with weaker effects on receptor function (43), may be of greater relevance by virtue of its higher prevalence in the population. Evidence for an association between Pro12Ala and T2DM was first reported in a population of middle-aged and elderly Finns, in whom a lower BMI appeared to correlate with improved insulin sensitivity in those carrying the Ala allele (43). In the same study, a significant odds ratio (4.35, P = 0.028) for the association of the Pro/Pro genotype with T2DM was observed among a group of second-generation Japanese Americans. However, this association was poorly reproducible, with only one of five subsequent studies showing statistically significant association with diabetes risk (63, 64, 65, 66, 67). Nevertheless, interest was rekindled when Altshuler et al. (40) undertook a meta-analysis of published association studies confirming a modest (1.25-fold) but significant (P = 0.002) increase in diabetes risk with the Pro allele. Thus, if an entire population carried the Ala allele, the global prevalence of T2DM would be reduced by 25%. The authors argued that collectively existing published data were consistent with their observed effect but with most individual studies having been underpowered, thereby leading earlier authors to inappropriately dismiss a role for Pro12Ala in diabetes risk.
An important reservation with this meta-analysis is the possibility that it may have been confounded by the problem of publication bias, favoring studies showing a positive association. Nevertheless, if its findings are accepted, it raises the question of exactly how the Ala genetic variant influences diabetes risk. In the original study of Deeb et al. (43), carriers of the Ala polymorphism had a significantly lower BMI, and after correcting for this, there was no difference in insulin sensitivity between genotypes. Having shown that the Ala receptor variant was less transcriptionally active, the authors hypothesized that reduced adipogenesis in individuals with the Ala allele, reflected in a lower BMI, might ultimately translate to improved insulin sensitivity. This hypothesis would unify the observation that PPAR2 has a unique regulatory role in adipogenesis (42), with the knowledge that body fat mass is a strong determinant of insulin sensitivity. However, subsequent studies have failed to yield consistent findings, with some even demonstrating a modestly greater BMI in carriers of the Ala allele (68, 69, 70). Together this suggests that the effects of Pro12Ala on fat mass and BMI are subtle and subject to modification by other genetic and environmental influences. For example, a recent study indicates that variations in dietary polyunsaturated fat vs. saturated fat intake can influence BMI in carriers of the Ala variant, suggesting gene-nutrient interaction at the PPAR locus (71).
The finding that a less transcriptionally active human receptor variant (Pro12Ala) predisposes to increased insulin sensitivity may also accord with observations in transgenic mouse models of PPAR action. Thus, two groups have shown that heterozygous PPAR null mice (±) exhibit increased insulin sensitivity, compared with their wild-type littermates (24, 72). As described previously, these animals have reduced fat depots, with lower levels of triglyceride accumulation and lipogenesis in white adipose tissue, skeletal muscle, and liver (25). It has, therefore, been proposed that a complex U-shaped curve best describes the relationship between PPAR activity and insulin sensitivity (52); thus, a modest reduction in receptor function and adipogenesis (as observed with the human Pro12Ala variant or heterozygous null mice) improves insulin action. Conversely, a modest increase in receptor activity (the human Pro115Gln mutation) might predispose to insulin resistance through promoting obesity. Such an assertion must, however, be highly tentative because only a small number of such subjects have been described; the genetic evidence for the causative nature of this mutation is weak with no family cosegregation data available; and although adiposity may be increased in subjects with the Pro115Gln mutation, fasting insulin levels in these subjects are relatively low for their degree of adiposity.
High levels of receptor activation by, for example, TZDs or other PPAR agonists, paradoxically improve insulin sensitivity despite enhancing adipogenesis (Fig. 2). We suggest that this model needs to be extended to encompass findings in subjects harboring loss-of-function mutations within the LBD of PPAR. Here more marked lipodystrophy and impairment of PPAR action is associated with a drastic reduction in insulin sensitivity, perhaps suggesting that the relationship might be sinusoidal rather than U-shaped (Fig. 2). Clearly such a model has its limitations, especially when it seeks to explain a complex biological trait such as insulin resistance in terms of variation at a single genetic locus. The complexity of this issue is graphically illustrated by a human pedigree we have described in which five individuals who were doubly heterozygous for frameshift/premature stop mutations in both PPAR and the muscle-specific regulatory subunit of protein phosphatase 1 (PPP1R3A) were severely insulin resistant and two subjects from that family who harbored only the PPAR mutation had relatively normal insulin sensitivity (73). Although the PPAR mutation in this family is not identical to the null allele in the heterozygous knockout mice, the human mutation does result in a prematurely truncated PPAR, which cannot bind DNA and does not appear to act as a dominant negative. We, therefore, feel it is premature to assume that the loss of one allele of PPAR in humans will necessarily directly parallel the beneficial effects on insulin sensitivity and certainly not when there are other coexistent genetic defects.
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PPAR and hypertension
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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). Its pathogenesis is complex and incompletely understood, but may well involve impaired insulin signaling in subjects with this disorder (74). TZDs reduce blood pressure in patients with T2DM and hypertension, nonhypertensive type 2 diabetics, obese subjects without diabetes, and nondiabetic hypertensives (75). Early-onset hypertension was also a prominent clinical finding in individuals with the Pro467Leu, Val290Met, and Arg425Cys PPAR mutations (32, 33). However, the absence of hypertension in two of the four carriers of the Phe388Leu mutation (34), together with the well-known association between hypertension and insulin resistance per se, suggests that this association may not be specific to PPAR mutant-associated insulin resistance. Although several lines of evidence suggest that PPAR may have direct effects on vascular tone, e.g. through blockade of calcium channel activity in smooth muscle (76), inhibition of release of endothelin-1 (77), and enhancement of C-type natriuretic peptide release (78), it is likely to be difficult to dissociate the indirect effects of PPAR on blood pressure via its insulin-sensitizing action from a direct vascular effect. A further problem in discerning the role of PPAR in human blood pressure regulation is the need to dissociate non-PPAR-mediated effects of TZDs from direct receptor dependent effects. For example, troglitazone mediates vasodilatation in human blood vessels isolated from adipose tissue, but rosiglitazone, a more potent and specific PPAR agonist, lacks these effects, suggesting that some of the vascular action of troglitazone may be non-PPAR mediated (79). |
PPAR and dyslipidemia
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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have raised triglycerides and low HDL levels, with unremarkable low-density lipoprotein (LDL) cholesterols (32, 33, 34, 35, 36). Hegele et al. (34) have suggested that the dyslipidemic phenotype in these subjects is milder than that seen in other patients with familial partial lipodystrophy because of lamin mutations. However, the number of affected individuals studied remains small, and given the ability of dietary indiscretion and poor glycemic control in diabetics to modify triglyceride levels, we feel that further data are required before any firm conclusions are drawn. Unfortunately, lipid profiles were not reported in the subjects with the gain-of-function Pro115Gln mutation and, in any event, three of the four subjects with this mutation were already diabetic, making interpretation of lipid parameters difficult.
PPAR agonists, which improve insulin sensitivity, would be expected to lower circulating triglycerides and raise HDL levels. Intriguingly, although pioglitazone does reduce triglycerides, rosiglitazone does not lower and may even slightly increase serum triglyceride levels. The mechanisms underlying the divergent responses to these TZDs remain to be elucidated. TZDs also increase LDL cholesterol, possibly through enhancing levels of large buoyant LDL particles. It has been suggested that this beneficial effect on particle size will translate into delayed progression of atheromatous disease. Ongoing long-term studies, designed to assess cardiovascular end points in TZD-treated patients, will yield more conclusive data on this effect.
TZDs may also lower FFA levels, which is of particular significance for two reasons: first, the so-called fatty acid steal hypothesis proposes that TZDs promote trapping and storage of FFAs within adipocytes (80), a circumstance bound to both increase fat mass and improve insulin sensitivity and dyslipidemia by reducing fatty acid flux to liver and skeletal muscle; second, the induction of glycerol kinase expression and activity in rodent and human adipocytes by TZDs, recently reported by Guan et al. (81), proposes a model in which these PPAR agonists promote a futile cycle within adipocytes resulting in reduced FFA release. Our own studies of a single subject harboring the P467L PPAR mutation suggest that adipose tissue in this individual was relatively metabolically inert, arguing that loss of metabolic flexibility, whereby adipose tissue can mobilize fatty acids in the fasting state and trap and store fatty acids postprandially, is important in the pathogenesis of insulin resistance in this receptor disorder (36). In keeping with this notion, measurement of fatty acid kinetics in rodents treated with PPAR agonists indicates that TZDs increase fasting FFA appearance as well as promoting insulin-stimulated FFA clearance (82). Overall, we, therefore, believe that it may be too simplistic to view TZDs as just lowering FFA levels and more comprehensive profiling of their effects on fatty acid fluxes in the fed and fasting state is necessary.
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PPAR and atherosclerosis
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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activation with exogenous ligands such as the TZDs would be predicted to confer significant benefits in this clinical setting by ameliorating insulin resistance, dyslipidemia, and possibly hypertension, albeit at a potential cost of mild weight gain as a consequence of enhanced adipogenesis. Although it is too early to know whether these theoretical benefits will translate into a genuine risk reduction in the longer term, early studies of carotid arterial intima-media thickness, a surrogate marker of atherosclerosis, have proved reassuring, reporting a significant reduction in subjects with T2DM treated with troglitazone and pioglitazone, respectively (83, 84).
It was, therefore, surprising and of potential therapeutic concern when Nagy et al. (18) and Tontonoz et al. (85) reported that PPAR activation in a premacrophage cell line induced expression of CD36, also known as fatty acid translocase, a cellular scavenger receptor for atherogenic LDL. Enhanced CD36 expression might be predicted to increase intracellular accumulation of oxidized LDL cholesterol, which could then be catabolized to generate PPAR ligands (e.g. 9-HODE and 13-HODE) capable of further receptor activation, thereby creating a vicious feed-forward cycle of increasing lipid uptake, ultimately driving conversion of the macrophage into an atherogenic foam cell. The finding that PPAR is expressed at relatively high levels in human atherosclerotic plaques further served to fuel concerns (86, 87).
However, almost coincident with these observations, several groups reported that PPAR ligands reduce the release of inflammatory cytokines (e.g. TNF- and IL-6) from macrophages, an effect that might be predicted to be antiatherogenic (88, 89). Subsequent studies have further redressed the balance, with the demonstration that PPAR ligands exert an opposing effect on SR-A, a second LDL scavenger receptor, down-regulating its expression in mouse macrophages (90). In addition, the nuclear receptor liver X receptor , which enhances expression of ATP-binding cassette transporter A1, a protein that mediates cellular cholesterol efflux (91), has also been shown to be a PPAR target gene in human and mouse macrophages (92, 93). Taken together, these data suggest a broader spectrum of PPAR effects within the macrophage with the overall balance favoring cholesterol efflux and an antiatherogenic effect.
According to this hypothesis, one might predict a predisposition to atheromatous vascular disease in subjects harboring loss-of-function mutations within the LBD of PPAR. However, of the eight affected adult subjects identified to date, only one (a male member of the Phe388Leu kindred) has been reported to suffer a vascular event (myocardial infarction at age 56 yr with no previous smoking history) (34). On the other hand, the majority of the other affected individuals are still relatively young (<50 yr) with a preponderance of females (five females, two males), suggesting that it may be premature to entirely exclude the possibility of accelerated vascular disease in this potentially high-risk group.
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Future developments |
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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in a ligand-dependent manner, mediate its transcriptional actions, in turn translating into the biological effects of the receptor. In addition to TZDs, a range of structurally unrelated ligands for PPAR have now been developed. Interestingly, when tested in vitro, different ligands have been shown to promote differing patterns of coactivator recruitment with, for example, RXR-specific ligands favoring SRC-1 binding, whereas TZDs promote association of the DRIP/TRAP220 cofactor with the PPAR-RXR heterodimer (94). Extrapolating these observations, it is conceivable that different PPAR ligands could induce dissimilar patterns of target gene expression.
With the major metabolic effects of PPAR being promotion of fat cell formation (adipogenesis) and enhancement of tissue sensitivity to insulin, this raises the intriguing possibility that it might be possible to uncouple these biological responses by developing selective receptor modulators, which preferentially affect glucose metabolism. Precedent for such an approach is provided by raloxifene, a selective estrogen receptor modulator, which is an estrogen receptor antagonist in breast and endometrium but an agonist in bone.
Promisingly, several groups have independently identified PPAR ligands with either partial agonist or antagonist activity, which exhibit divergent biological responses: GW0072 and LG100641 are compounds that inhibit adipocyte differentiation yet stimulate cellular glucose uptake (95, 96); FMOC-L-leucine, a chemically distinct receptor ligand, has been shown to improve insulin sensitivity yet exert relatively weak adipogenic effects in rodent diabetic models (97).
Fluid retention is an uncommon but undesirable complication of TZD therapy. As yet, it is unclear whether this side effect is linked to insulin sensitization or whether it may reflect PPAR action in the renal tubule. Conversely, enhancing the ability of TZDs to further alter the dyslipidemic profile of insulin resistance would clearly offer added therapeutic advantage in a high-risk T2DM population. A greater understanding of the PPAR target genes that mediate these effects, in conjunction with studies of patterns of cofactor recruitment and gene activation in response to novel receptor ligands, may lead to the development of newer agents that modulate beneficial PPAR responses with greater selectivity.
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Acknowledgments |
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Footnotes |
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M.G. and D.B.S. contributed equally to this work.
Abbreviations: BMI, Body mass index; FFA, free fatty acid; HDL, high-density lipoprotein; HODE, hydroxyoctadecadienoic acid; LBD, ligand-binding domain; LDL, low-density lipoprotein; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione.
Received March 12, 2003.
Accepted March 13, 2003.
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TopAbstractIntroductionThe metabolic syndromePPAR{gamma}: a nuclear receptorPPAR{gamma} and adipogenesisPPAR{gamma} and insulin...PPAR{gamma} and hypertensionPPAR{gamma} and dyslipidemiaPPAR{gamma} and atherosclerosisFuture developmentsReferences |
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ligand inhibits adipocyte differentiation. Proc Natl Acad Sci USA 96:6102–6106This article has been cited by other articles:
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 T.-C. Ho, S.-L. Chen, Y.-C. Yang, C.-L. Liao, H.-C. Cheng, and Y.-P. Tsao PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells Cardiovasc Res, November 1, 2007; 76(2): 213 - 223. [Abstract] [Full Text] [PDF]
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 L. Palanker, A. S. Necakov, H. M. Sampson, R. Ni, C. Hu, C. S. Thummel, and H. M. Krause Dynamic regulation of Drosophila nuclear receptor activity in vivo Development, September 15, 2006; 133(18): 3549 - 3562. [Abstract] [Full Text] [PDF]
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 A. G. Smith and G. E. O. Muscat Orphan nuclear receptors: therapeutic opportunities in skeletal muscle Am J Physiol Cell Physiol, August 1, 2006; 291(2): C203 - C217. [Abstract] [Full Text] [PDF]
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 P. Iglesias and J. J Diez Peroxisome proliferator-activated receptor gamma agonists in renal disease. Eur. J. Endocrinol., May 1, 2006; 154(5): 613 - 621. [Abstract] [Full Text] [PDF]
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 P Froment, F Gizard, D Defever, B Staels, J Dupont, and P Monget Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition. J. Endocrinol., May 1, 2006; 189(2): 199 - 209. [Abstract] [Full Text] [PDF]
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 J. Lopez-Soriano, C. Chiellini, M. Maffei, P. A. Grimaldi, and J. M. Argiles Roles of Skeletal Muscle and Peroxisome Proliferator-Activated Receptors in the Development and Treatment of Obesity Endocr. Rev., May 1, 2006; 27(3): 318 - 329. [Abstract] [Full Text] [PDF]
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 B. Desvergne, L. Michalik, and W. Wahli Transcriptional Regulation of Metabolism Physiol Rev, April 1, 2006; 86(2): 465 - 514. [Abstract] [Full Text] [PDF]
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 R. M. Najarian, L. M. Sullivan, W. B. Kannel, P. W. F. Wilson, R. B. D'Agostino, and P. A. Wolf Metabolic Syndrome Compared With Type 2 Diabetes Mellitus as a Risk Factor for Stroke: The Framingham Offspring Study Arch Intern Med, January 9, 2006; 166(1): 106 - 111. [Abstract] [Full Text] [PDF]
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 A. Meirhaeghe, D. Cottel, P. Amouyel, and J. Dallongeville Association Between Peroxisome Proliferator-Activated Receptor {gamma} Haplotypes and the Metabolic Syndrome in French Men and Women Diabetes, October 1, 2005; 54(10): 3043 - 3048. [Abstract] [Full Text] [PDF]
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 A. I. Shulman and D. J. Mangelsdorf Retinoid X Receptor Heterodimers in the Metabolic Syndrome N. Engl. J. Med., August 11, 2005; 353(6): 604 - 615. [Full Text] [PDF]
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 D. Hamerman Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies QJM, July 1, 2005; 98(7): 467 - 484. [Abstract] [Full Text] [PDF]
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 C. Yu, K. Markan, K. A. Temple, D. Deplewski, M. J. Brady, and R. N. Cohen The Nuclear Receptor Corepressors NCoR and SMRT Decrease Peroxisome Proliferator-activated Receptor {gamma} Transcriptional Activity and Repress 3T3-L1 Adipogenesis J. Biol. Chem., April 8, 2005; 280(14): 13600 - 13605. [Abstract] [Full Text] [PDF]
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 R. K. Semple, A. Meirhaeghe, A. J. Vidal-Puig, J. W. R. Schwabe, D. Wiggins, G. F. Gibbons, M. Gurnell, V. K. K. Chatterjee, and S. O'Rahilly A Dominant Negative Human Peroxisome Proliferator-Activated Receptor (PPAR){alpha} Is a Constitutive Transcriptional Corepressor and Inhibits Signaling through All PPAR Isoforms Endocrinology, April 1, 2005; 146(4): 1871 - 1882. [Abstract] [Full Text] [PDF]
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A. Sandelin and W. W. Wasserman Prediction of Nuclear Hormone Receptor Response Elements Mol. Endocrinol., March 1, 2005; 19(3): 595 - 606. [Abstract] [Full Text] [PDF]
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S. Redondo, E. Ruiz, C. G. Santos-Gallego, E. Padilla, and T. Tejerina Pioglitazone Induces Vascular Smooth Muscle Cell Apoptosis Through a Peroxisome Proliferator-Activated Receptor-{gamma}, Transforming Growth Factor-{beta}1, and a Smad2-Dependent Mechanism Diabetes, March 1, 2005; 54(3): 811 - 817. [Abstract] [Full Text] [PDF]
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 A. Ceriello, D. Johns, M. Widel, D. J. Eckland, K. J. Gilmore, and M. H. Tan Comparison of Effect of Pioglitazone With Metformin or Sulfonylurea (Monotherapy and Combination Therapy) on Postload Glycemia and Composite Insulin Sensitivity Index During an Oral Glucose Tolerance Test in Patients With Type 2 Diabetes Diabetes Care, February 1, 2005; 28(2): 266 - 272. [Abstract] [Full Text] [PDF]
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 A. C. Li and C. K. Glass PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis J. Lipid Res., December 1, 2004; 45(12): 2161 - 2173. [Abstract] [Full Text] [PDF]
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 K. Al-Shali, H. Cao, N. Knoers, A. R. Hermus, C. J. Tack, and R. A. Hegele A Single-Base Mutation in the Peroxisome Proliferator-Activated Receptor {gamma}4 Promoter Associated with Altered in Vitro Expression and Partial Lipodystrophy J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5655 - 5660. [Abstract] [Full Text] [PDF]
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 Y. Guan Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2801 - 2815. [Abstract] [Full Text] [PDF]
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S. Sinha, G. Perdomo, N. F. Brown, and R. M. O'Doherty Fatty Acid-induced Insulin Resistance in L6 Myotubes Is Prevented by Inhibition of Activation and Nuclear Localization of Nuclear Factor {kappa}B J. Biol. Chem., October 1, 2004; 279(40): 41294 - 41301. [Abstract] [Full Text] [PDF]
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 L. E. Parton, F. Diraison, S. E. Neill, S. K. Ghosh, M. A. Rubino, J. E. Bisi, C. P. Briscoe, and G. A. Rutter Impact of PPAR{gamma} overexpression and activation on pancreatic islet gene expression profile analyzed with oligonucleotide microarrays Am J Physiol Endocrinol Metab, September 1, 2004; 287(3): E390 - E404. [Abstract] [Full Text] [PDF]
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Z. He, T. Jiang, Z. Wang, M. Levi, and J. Li Modulation of carbohydrate response element-binding protein gene expression in 3T3-L1 adipocytes and rat adipose tissue Am J Physiol Endocrinol Metab, September 1, 2004; 287(3): E424 - E430. [Abstract] [Full Text] [PDF]
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 M. M. Masternak, K. Al-Regaiey, M. S. Bonkowski, J. Panici, L. Sun, J. Wang, G. K. Przybylski, and A. Bartke Divergent Effects of Caloric Restriction on Gene Expression in Normal and Long-Lived Mice J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2004; 59(8): B784 - B788. [Abstract] [Full Text] [PDF]
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H. R. Kast-Woelbern, S. L. Dana, R. M. Cesario, L. Sun, L. Y. de Grandpre, M. E. Brooks, D. L. Osburn, A. Reifel-Miller, K. Klausing, and M. D. Leibowitz Rosiglitazone Induction of Insig-1 in White Adipose Tissue Reveals a Novel Interplay of Peroxisome Proliferator-activated Receptor {gamma} and Sterol Regulatory Element-binding Protein in the Regulation of Adipogenesis J. Biol. Chem., June 4, 2004; 279(23): 23908 - 23915. [Abstract] [Full Text] [PDF]
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B. Desvergne, L. Michalik, and W. Wahli Be Fit or Be Sick: Peroxisome Proliferator-Activated Receptors Are Down the Road Mol. Endocrinol., June 1, 2004; 18(6): 1321 - 1332. [Abstract] [Full Text] [PDF]
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E. S. Tai, D. Corella, M. Deurenberg-Yap, X. Adiconis, S. K. Chew, C. E. Tan, and J. M. Ordovas Differential effects of the C1431T and Pro12Ala PPAR{gamma} gene variants on plasma lipids and diabetes risk in an Asian population J. Lipid Res., April 1, 2004; 45(4): 674 - 685. [Abstract] [Full Text] [PDF]
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