Ppar[gamma] as a metabolic regulator: insights from genomics and pharmacology

expert reviews
PPARγ as a metabolic regulator:
insights from genomics and
pharmacology
pharmacology
David B. Savage
Since its identification in the early 1990s, peroxisome-proliferator-activated
receptor γ (PPARγ), a nuclear hormone receptor, has attracted tremendous
scientific and clinical interest. The role of PPARγ in macronutrient metabolism
has received particular attention, for three main reasons: first, it is the target of
the thiazolidinediones (TZDs), a novel class of insulin sensitisers widely used
genomics and
to treat type 2 diabetes; second, it plays a central role in adipogenesis; and
third, it appears to be primarily involved in regulating lipid metabolism with
predominantly secondary effects on carbohydrate metabolism, a notion in
keeping with the currently in vogue ‘lipocentric’ view of diabetes. This review
summarises in vitro studies suggesting that PPARγ is a master regulator of
adipogenesis, and then considers in vivo findings from use of PPARγ agonists,
knockout studies in mice and analysis of human PPARγ mutations/
γ as a metabolic regulator: insights from
polymorphisms.
Given Western society’s propensity for over- which have a very limited capacity to expand, eating and under-exercising, the major energetic hydrophobic TG droplets are a much more efficient way to store energy and have considerable storage of excess calories. This energy overload potential for expansion. Although this ultimately is predominantly disposed of as triglyceride (TG) predisposes over-nourished humans to weight in white adipose tissue. The average adipose tissue gain, in the short to medium term it represents an mass of a 70 kg adult human is ∼12 kg, representing efficient metabolic response to fluctuating energy an energy store of ∼352 MJ (∼84 000 kcal). By contrast, carbohydrate stores in the form of glycogen in The importance of the capacity to store excess liver and skeletal muscle account for only ∼6.7 MJ energy in adipocytes is epitomised by the (∼1600 kcal). Unlike hydrophilic glycogen stores, metabolic consequences of a loss of adipose David B. SavageWellcome Clinician Scientist, Departments of Medicine and Clinical Biochemistry, University ofCambridge, UK.
Current address: Yale University School of Medicine, S260 TAC, 1 Gilbert Street, New Haven, CT06520-8020, USA. Tel: +1 203 737 5679; Fax: +1 203 785 3823; E-mail: [email protected] Institute URL: http://www.clbc.cam.ac.uk/ Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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tissue, as seen in lipodystrophy (Ref. 1). The to facilitate appropriate storage of excess calories in adipose tissue, to modify signals from adipose heterogeneous group of conditions characterised tissue to the brain and other tissues regarding the by partial or complete absence of adipose tissue status of these energy stores, and to limit ectopic due to a lack of functional adipocytes (usually as lipid accumulation in sites such as the liver and a result of genetic or immunological mechanisms) (Ref. 2). Lipodystrophy is distinct from leanness, PPARγ has also been implicated in inflammatory as in that case adipose storage can readily be responses and carcinogenesis, but these roles are normalised or even increased above normal by not covered here – for recent comprehensive pharmacology
the restoration of a positive energy balance. In lipodystrophic subjects with a significantlyreduced adipose tissue storage capacity, positive energy balance is thought to lead to ‘ectopic’ fat deposition (i.e. lipid deposition in tissues other receptor superfamily. Its name stems from the than fat, such as the liver and skeletal muscle), identification in 1990 of a homologue, PPARα, insulin resistance and ultimately diabetes.
that mediates the exuberant proliferation of Interestingly, obesity is also associated with hepatic peroxisomes in mice exposed to various ectopic lipid accumulation, insulin resistance and diabetes; in this case it is thought that energy homologues were later cloned in Xenopus (Ref. 12) intake ultimately exceeds the capacity of adipose and then in all mammalian species studied, the genomics and
tissue to expand, leading to ‘overflow’ to ectopic three receptors were designated PPARα, PPARδ As well as needing to be able to adapt to long- term changes in energy balance, humans have to Structure and transcriptional activity
cope with the energy load associated with There are two protein splice isoforms of PPARγ: consumption of three daily meals. Failure to PPARγ1 and PPARγ2 (Ref. 13). PPARγ2 has 30 dispose efficiently of ingested carbohydrate and additional N-terminal amino acids compared with fat would lead to large changes in plasma glucose PPARγ1 in humans (28 in mice), and is expressed and TG. In healthy humans, the liver and skeletal only in adipose tissue. Two additional mRNA muscle effectively buffer ingested carbohydrate, splice variants PPARγ3 (Ref. 14) and PPARγ4 γ as a metabolic regulator: insights from
while adipose tissue plays a key role in buffering (Ref. 15) give rise to proteins identical to PPARγ1.
postprandial TGs (Ref. 3). Triggered by the The biological relevance of these mRNA variants discovery of leptin in 1994 (Ref. 4), research over the past decade has yielded significant insight into receptors, PPARγ contains an N-terminal domain the complexity of adipocyte differentiation and with a ligand-independent AF-1 activation the mechanisms by which adipose tissue copes domain, a central DNA-binding domain (DBD) with both short- and long-term perturbations in composed of two zinc fingers, and a C-terminal energy balance (Ref. 5). In ‘times of excess’, ligand-binding and dimerisation domain (LBD) adipose tissue responds by increasing both the with a ligand-dependent AF-2 transactivation number of mature adipocytes by adipogenesis (the differentiation of stromal fibroblast-like pre- In the absence of ligand, PPARγ can bind to adipocytes into mature lipid-laden adipocytes) co-repressors (proteins that lead to condensation and the size of pre-existing cells (hypertrophy). It of chromatin and sequestration of promoter is also capable of signalling the state of its stores elements), which inhibit transcriptional activity by secreting proteins such as leptin (Ref. 6).
in a DNA-independent manner. All PPARs bind Peroxisome-proliferator-activated receptor γ DNA as heterodimers with retinoid X receptor (PPARγ) is one of several transcription factors (RXR). Ligand binding to either PPAR or RXR regulating adipocyte number and size (see induces conformational changes in the PPAR– Ref. 7 for details of other transcription factors RXR heterodimer, favouring release of co- involved in this regulation). It is also involved in repressor molecules and recruitment of co- modulating secretion of several ‘adipokines’ (a activator proteins, which facilitate access and collective term for proteins secreted by adipose assembly of a transcriptional regulatory complex tissue) (Ref. 8) and is therefore uniquely placed (Fig. 1b). This complex binds to specific PPAR Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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PPARγ structure and mode of gene regulation Expert Reviews in Molecular Medicine C 2005 Cambridge University Press genomics and
Figure 1. PPARγ structure and mode of gene regulation. (a) PPARγ (peroxisome-proliferator-activated
receptor γ) has the typical nuclear hormone receptor domain structures, including a central DNA-binding domain,
a C-terminal ligand-binding domain, and two activation domains (AF-1, ligand-independent activation domain;
AF-2, ligand-dependent activation domain). PPARγ1 and 2 are identical except for an additional 30 amino acid
N-terminal extension in PPARγ2 (not shown). (b) PPARγ binds to PPAR response elements (PPREs) as an
obligate heterodimer with the retinoid X receptor (RXR). Ligand binding to either PPAR or RXR induces
displacement of co-repressors, recruitment of co-activators and transcriptional activation of target genes.
response elements (PPREs) in the promoter response to fasting (Ref. 19). PPARδ is abundantly γ as a metabolic regulator: insights from
regions of target genes (see Ref. 16 for a detailed expressed in almost all tissues. Its precise review of the mechanism of transcriptional biological role is less well understood than those of PPARα and PPARγ, but recent work suggeststhat it is a potent inducer of fatty acid oxidation Tissue distribution
and that PPARδ agonists improve plasma lipid PPARγ is most highly expressed in both white and brown adipose tissue. The PPARγ2 isoform isalmost exclusive to adipose tissue, where it constitutes about 30% of the total PPARγ, whereas Whereas membrane-bound receptors are generally PPARγ1 is also readily detectable in large intestine responsible for propagating signals initiated by and haematopoietic cells, and is expressed at low hydrophilic protein molecules, the nuclear levels in liver, skeletal muscle, pancreas and most hormone receptor superfamily is responsible for other tissues (Refs 13, 17). In rodents, PPARγ signalling by lipophilic molecules, including expression is reduced after an overnight fast and steroids and derivatives thereof, and fatty acids in insulin-deficient streptozotocin-induced and their derivatives. Changes in concentration diabetes, suggesting that insulin might be of lipid moieties are ‘sensed’ by these receptors, involved in stimulating PPARγ expression (Ref. 18).
which respond by modifying gene transcription It is of interest to compare the tissue distribution in the host cell. The precise nature of the of PPARγ with that of PPARα and of PPARδ for endogenous PPARγ ligand(s) has been the subject insight into their respective biological roles.
of much, as yet unresolved, debate. Naturally PPARα is most highly expressed in muscle occurring fatty acids and eicosanoids can bind and (especially in humans) and liver, where it activate all three PPARs. However, most of these regulates fatty acid oxidation and the metabolic naturally occurring ligands bind with relatively Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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low affinity compared with the affinity of well- products of these genes can be grouped functionally established ligands for other nuclear receptors.
into: (1) proteins involved in hydrolysis of plasma They also exist at very low concentrations in vivo TGs, fatty acid uptake and esterification, lipogenesis (Ref. 21) and are weak agonists, raising doubts and TG synthesis; (2) proteins regulating lipolysis; about their biological relevance. Tzameli et al.
(3) adipokines; and (4) proteins directly implicated recently identified a higher-affinity lipophilic in insulin signalling and glucose uptake (Table 1).
PPARγ-specific ligand, which was transiently These targets suggest that PPARγ influences lipid produced in differentiating 3T3L1 pre-adipocytes and glucose metabolism within adipocytes (Fig. 2), (Ref. 22). Further work is required to establish the as well as signalling from adipose tissue.
pharmacology
exact nature of this molecule(s) and to determine PPARγ agonists also reduce 11β-hydroxysteroid its relevance to the biological role of PPARγ in dehydrogenase 1 expression (11β-HSD1) in adipose mature adipocytes and other sites such as liver tissue (Ref. 25). 11β-HSD1 converts inactive cortisone to bioactive corticosterone within tissues, Several high-affinity synthetic PPARγ agonists and overexpression of this gene in mouse adipose are available. They include thiazolidinediones tissue induces a ‘Cushingoid state’ in mice, with (TZDs), which were identified as part of a drug- central obesity, insulin resistance and hypertension screening process for antidiabetic compounds (Ref. 26). Hence, suppression of 11β-HSD1 by (Ref. 23) and only later found to act via PPARγ, PPARγ agonists might contribute to their insulin- as well as several more recently identified compounds such as tyrosine-based agonists Key in vitro observations:
genomics and
(Ref. 24). This is an area of intense interest to thepharmaceutical industry, which is pursuing both PPARγ and adipogenesis
dual- and pan-PPAR agonists (i.e. compounds PPARγ is abundantly expressed in adipocytes capable of activating combinations of PPARγ, and its expression is markedly induced during PPARα and PPARδ) and so-called selective PPARγ adipocyte differentiation (Ref. 27), prompting modulators (SPPARMs), with both agonist and questions about its role in adipogenesis and in antagonist activity (see section on SPPARMs mature adipocytes. Overexpression of PPARγ in pre-adipocytes is sufficient for adipogenesis, evenin the absence of CCAAT/enhancer-binding protein Target genes
alpha (C/EBPα), another key transcriptional γ as a metabolic regulator: insights from
The number of genes directly and indirectly regulator of adipogenesis (Ref. 28). By contrast, regulated by PPARγ continues to expand. The murine embryo fibroblasts (MEFs) lacking PPARγ Table 1. Gene targets of PPARγ
Function
Examples
Fatty-acid-binding protein 4 (aP2)AcylCoA synthase Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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PPARγ target genes and adipocyte metabolism Expert Reviews in Molecular Medicine C 2005 Cambridge University Press Figure 2. PPARγ target genes and adipocyte metabolism. PPARγ (peroxisome-proliferator-activated
receptor γ) regulates adipocyte metabolism through effects on the transcription of several genes. In the figure,
PPARγ-regulated gene products promoting lipid storage are highlighted in green, whereas those promoting
γ as a metabolic regulator: insights from
lipolysis are highlighted in red (see also Table 1). Plasma triglyceride (TG) is hydrolysed by lipoprotein lipase(LPL) to nonesterified fatty acid (NEFA) and glycerol. NEFA uptake by adipocytes is probably aided by the transporters CD36 and fatty-acid-transport protein (FATP); the aquaporin channel facilitates glycerol transport.
In adipocytes, NEFAs are re-esterified via the action of acylCoA synthase (ACS) for storage as TG, while glycerol is converted to glycerol 3-phosphate (G3P) by the action of glycerol kinase (GK). In addition, G3P canbe synthesised via the action of phosphoenolpyruvate carboxykinase (PEPCK) (glyceroneogenesis) (dashedlines imply several intermediate steps; PEP, phosphoenolpyruvate). Thus, PPARγ may promote TG synthesisby inducing transcription of genes involved in regulating plasma lipid uptake (LPL, CD36, FATP, aquaporin)and metabolism within the adipocyte (ACS, GK, PEPCK). [Note, however, that GK does not appear to beinduced by thiazolidinediones in humans (Ref. 61)]. PPARγ can also influence lipolysis by inducing perilipinexpression [perilipin is an important determinant of hormone-sensitive lipase (HSL) activity].
are unable to differentiate into adipocytes even that PPARγ2 is the most important isoform in in the presence of overexpressed C/EBPα, adipogenesis. Another group obtained different suggesting that PPARγ is the master regulator of results using a similar experimental paradigm adipocyte differentiation (Ref. 29).
(Ref. 31); their data suggested that adipogenic In order to examine the relative importance of capacity could be restored to PPARγ-null pre- PPARγ1 and PPARγ2 in adipogenesis, retroviruses adipocytes by overexpressing either PPARγ1 or were used to restore expression of either PPARγ1 PPARγ2. However, they also found that the pro- or PPARγ2 to PPARγ-null pre-adipocytes (Ref. 30).
adipogenic activity of PPARγ2 was greater than that of PPARγ1. This notion is supported by the comparable levels, only PPARγ2 was able to phenotype of PPARγ2-isoform-specific knockout rescue the adipogenic phenotype, suggesting mice, which have a form of partial lipodystrophy Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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(Ref. 32). Pre-adipocytes isolated from adipose for a week before insulin sensitivity and fatty acid tissue of these mice also fail to differentiate in disposal were assessed during a TG–heparin infusion (Ref. 38). As expected, rosiglitazoneimproved insulin sensitivity and increased fatty Animal in vivo observations
acid uptake into adipose tissue (twofold), while Rodents have been used to explore the metabolic reducing fatty acid uptake into liver and muscle response to PPARγ agonists in vivo, and to assess the consequences of altering PPARγ expression in Taken together, these data suggest that PPARγ both the whole organism and in a tissue-specific activation enhances metabolic flexibility by pharmacology
appropriately facilitating disposal of lipids inadipose tissue in the fed state and FFA turnover Use of PPARγ agonists in rodents
in the fasting state (i.e. release of FFAs from Intriguingly, TZDs tend to increase fat mass as adipocytes and their subsequent oxidation).
well as improving insulin sensitivity and This capacity to synchronise lipid metabolism glucose tolerance in rodents and humans. The appropriately with nutrient ingestion is a vital conventional explanation for these seemingly element of normal metabolism in which: (1) discordant effects is that TZDs promote lipid postprandial insulin release facilitates glucose uptake and storage in adipose tissue [‘fatty acid uptake and oxidation, glycogen synthesis and steal’ hypothesis (Ref. 33)], thereby lowering lipid disposal in adipose tissue; and (2) FFAs are systemic free fatty acid (FFA) levels and reducing released by adipocytes in the fasting state when genomics and
FFA delivery to other tissues where they have lipid oxidation becomes a key energy source.
been implicated in inducing insulin resistance(Ref. 34) (Fig. 3). In fact, detailed studies of FFA PPARγ-knockout models
and TG metabolism indicate that the mode of PPARγ−/−
action of TZDs is more complex than a simple PPARγ-knockout mice die in utero as a result lowering of plasma FFAs. Lipid turnover was of placental insufficiency (Ref. 39). Rescue of initially studied in obese insulin-resistant Zucker rats (fa/fa) treated with TZDs for three weeks tetraploid PPARγ+/+ pre-implantation embryos (Ref. 35). Rather than a global reduction in ultimately resulted in a single live-born plasma FFAs, the authors observed reduced PPARγ-null mouse that lacked almost all white γ as a metabolic regulator: insights from
plasma FFA levels in TZD-treated rats exposed to and brown adipose tissue (Ref. 39). Another group hyperinsulinaemia approximating postprandial (Ref. 40) circumvented the problem of placental levels, and, surprisingly, elevated FFA rates of insufficiency by injecting PPARγ-null embryonic appearance in the basal (fasting) state of treated stem cells into wild-type blasts. They found that animals. The increase in fasting FFA rates of PPARγ-null cells contributed very little if anything appearance was not, however, associated with to adipose tissue in these mice, supporting the elevated plasma FFAs because of a corresponding notion that PPARγ is a key determinant of adipose increase in FFA clearance. Basal FFA oxidation was substantially increased (approximately 50%),while insulin-mediated suppression of fatty PPARγ+/−
acid oxidation was greatly enhanced. Plasma TG If PPARγ agonists improve insulin sensitivity and levels were also significantly reduced by TZDs, PPARγ is essential for adipogenesis, one might primarily as a result of accelerated conversion of have expected PPARγ+/− heterozygous mice to be TG-rich very-low-density lipoprotein (VLDL) to either normal or to have a form of partial TG-poor lipoprotein remnants. These changes in lipodystrophy and insulin resistance. Instead, TG and FFA flux are associated with changes in they are protected against both high-fat-diet- adipose tissue morphology; typically, higher induced insulin resistance and ageing-associated numbers of smaller adipocytes are seen in TZD- insulin resistance (Refs 37, 41). This apparent treated rodents (Refs 36, 37). TG content in liver improvement in insulin sensitivity has been and muscle was also significantly reduced (Ref. 35).
attributed to a reduction in adipocyte size and increased leptin expression. Smaller adipocytes demonstration of the ‘lipid steal hypothesis’, are consistently more sensitive to insulin than are normal rats were treated with a TZD (rosiglitazone) larger adipocytes (Refs 42, 43), and, in addition Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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γ as a metabolic regulator: insights from
Expert Reviews in Molecular Medicine C 2005 Cambridge University Press Figure 3. Thiazolidinediones and lipotoxicity. Under normal circumstances (a), energy that is not immediately
utilised is stored as triglyceride in adipose tissue. Ingestion of excess energy (b) results in adipocyte hyperplasia
and hypertrophy, but some of the excess energy is diverted to other tissues such as liver and skeletal musclewhere it is believed to induce insulin resistance (so-called ‘lipotoxicity’). PPARγ (peroxisome-proliferator-activatedreceptor γ) agonists (c) increase the number of small, insulin-sensitive adipocytes. This might lead to weightgain but concurrently lowers ectopic lipid accumulation in liver and skeletal muscle, and improves insulin action.
to appetite suppression, leptin might have PPARγLoxP mice with aP2-Cre mice) manifest peripheral insulin-sensitising properties that are progressive lipodystrophy (Ref. 46). They are anti-steatotic (preventing fat accumulation in liver also more susceptible to high-fat-diet-induced and muscle) (Ref. 44). Treating PPARγ+/− mice with insulin resistance (particularly hepatic insulin either PPARγ antagonists or RXR antagonists resistance), dyslipidaemia and hepatic steatosis induced lipodystrophy and insulin resistance, than wild-type littermates. Interestingly, suggesting that although partial PPARγ deficiency although TZD therapy failed to lower FFAs in fat- might be metabolically beneficial, any additional specific PPARγ-knockout mice, it improved loss of PPARγ function is deleterious (Ref. 45).
hepatic insulin sensitivity, suggesting that thiseffect of TZDs is, at least in part, independent Tissue-specific knockouts
of PPARγ activity in adipose tissue. The relative PPARγ has been knocked out in each of the key importance of PPARγ in adipose tissue in insulin-sensitive tissues in mice. Fat-specific mediating the metabolic response to TZDs has PPARγ-knockout mice (generated by crossing also been examined by treating mice without Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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any adipose tissue (i.e. lipodystrophic mice) Inflammation in adipose tissue
with TZDs (Refs 47, 48). The re s p o n s e i s somewhat variable depending upon the extent PPARγ could alter metabolism involves the of the lipodystrophy and the background rodent recently described inflammatory response within strain, but in general it is less dramatic than that adipose tissue in obese rodents and humans.
seen in mice with adipose tissue, emphasising the Macrophages constitute a significant proportion importance of adipose tissue in TZD action; of the stromovascular fraction of adipose tissue however, the fact that lipodystrophic mice can and their numbers are significantly increased in respond does suggest that PPARγ might also be obese states, where they appear to make a pharmacology
biologically active in other tissues.
substantial contribution to gene expression within Muscle-specific PPARγ-knockouts have been adipose tissue (Refs 54, 55). Whether this generated by two independent groups. According inflammatory infiltrate is responsible for the to Hevener et al. (Ref. 49), muscle-specific PPARγ- development of insulin resistance in obese states knockout mice weigh more than wild-type mice, is not yet clear, although Xu et al. (Ref. 54) did and manifest insulin resistance (whole-body suggest that the increase in inflammatory gene and muscle), dyslipidaemia and fatty liver.
expression within adipose tissue preceded the TZDs improve whole-body insulin sensitivity, dramatic increase in plasma insulin levels dyslipidaemia and fatty liver in these mice but noted in high-fat-fed mice. They also reported fail to improve muscle insulin sensitivity. Norris downregulation of these macrophage-derived et al. (Ref. 50) also detected obesity and whole- genes in response to treatment with TZDs. This genomics and
body insulin resistance in muscle-specific PPARγ- observation is in keeping with the reported knockout mice but, unlike Hevener et al. (Ref. 49), increase in inflammation within adipose tissue of they suggested that muscle insulin sensitivity was adipocyte-specific PPARγ-knockout mice (Ref. 46).
within normal limits. They also noted that the Although much work remains to be done in this area, PPARγ is expressed at significant levels in wild-type mice, seemingly suggesting that macrophages (Ref. 56) and it might provide yet PPARγ expression in muscle was not required for another mechanism by which PPARγ affects TZD action. The differences in muscle insulin sensitivity between these studies are importantas both studies set out to determine the biological Human studies
γ as a metabolic regulator: insights from
relevance of PPARγ expression in muscle.
Use of PPARγ agonists in humans
Mice lacking PPARγ in the liver have an increase In insulin-resistant humans, TZDs improve in fat mass, dyslipidaemia and insulin resistance insulin sensitivity and glucose tolerance (Ref. 57).
(Refs 51, 52). Crossing these mice with lipodystrophic Pioglitazone also lowers TGs and raises high- AZIP mice (Ref. 51) or leptin-deficient ob/ob mice density lipoprotein (HDL), whereas rosiglitazone (Ref. 52) lowers liver TGs but worsens muscle has no effect on fasting TGs (Refs 57, 58, 59).
insulin resistance and dyslipidaemia, suggesting Pioglitazone’s capacity to lower TGs is probably that PPARγ in the liver might be involved in a result of weak PPARα agonist activity (Ref. 60).
limiting plasma hypertriglyceridaemia and excess Although TZDs are also frequently said to lower lipid delivery to skeletal muscle. This might, FFAs (Ref. 57), this observation is not universally however, come at the cost of hepatic steatosis, at accepted (Refs 59, 61) and might be a little least in circumstances in which the excess lipids simplistic. Recently reported studies in humans suggest that whereas rosiglitazone does not lower nonlipodystrophic mice, loss of hepatic PPARγ fasting FFAs and TGs in type 2 diabetics, it does does not alter the response to TZD treatment, lower postprandial FFAs and TGs (Ref. 59). The suggesting that liver PPARγ is not essential for capacity to improve insulin sensitivity also Targeted elimination of PPARγ in pancreatic β polycystic ovary syndrome (Ref. 62). However, cells does not alter glucose homeostasis but does there is a cost to pay for the metabolic benefits – affect β-cell proliferation (Ref. 53). This is in namely weight gain. In fact, the extent of keeping with the regulatory role of PPARγ in metabolic improvement is often proportional to adipocyte differentiation and carcinogenesis weight gain. Fluid retention (an ill-understood side effect of TZDs), reduced urinary caloric losses Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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in the form of glucosuria in diabetics, and an and/or other tissues such as the liver, a fact that increase in fat mass all contribute to the weight makes it difficult to discern the biological gain. The increase in fat mass is also associated importance of the fraction of these proteins with fat redistribution between adipose tissue produced by adipose tissue. Adipokines probably depots [from visceral to subcutaneous depots have a role in altering insulin action in disease (Ref. 57), and from the liver, and arguably muscle, states such as sepsis, but their role outside such to adipose tissue (Refs 63, 64)]. Insulin sensitivity states remains unproven in humans. Perhaps the is consequently improved in both liver and most exciting candidate in this class of proteins is adiponectin, which is almost exclusively pharmacology
Taken together, these observations suggest that produced by adipocytes and whose plasma levels the key component in the insulin-sensitising are regulated by TZDs (Refs 70, 71; see Ref. 72 for activity of PPARγ agonists is postprandial lipid trapping and storage in adipose tissue, withsecondary improvements in insulin-stimulated Human genetic variants
suppression of hepatic glucose output and glucose N-terminal mutations/polymorphisms
disposal in skeletal muscle. However, TZDs might Several mutations have been identified in the also have direct effects on insulin signalling PPARG gene, providing novel insights into the intermediates. Increases in expression of insulin biological role of PPARγ in humans (Fig. 4). By receptor substrate 2 (IRS2) (Ref. 65) and the far the most common variant is specific to PPARγ2 glucose transporter GLUT4 (Ref. 66) have been and results in a proline to alanine substitution at genomics and
reported in subjects treated with TZDs, suggesting position 12 (Pro12Ala) (minor allele frequency is that, in addition to indirect consequences of about 12% in Caucasians). Carriers of the Ala changes in lipid metabolism, PPARγ might also variant, which has less transcriptional activity have direct effects on glucose metabolism.
than the Pro form, were originally reported to be Saltiel and others have recently described a leaner than Pro carriers and to be protected against so-called second signalling pathway by which diabetes (Ref. 73). Although subsequent studies insulin receptor phosphorylation ultimately failed to verify the initial observation, a meta- induces GLUT4 translocation to the plasma analysis undertaken by Altshuler et al. (Ref. 74) membrane and subsequent glucose transport reported a modest (1.25-fold) but statistically (Ref. 67). In addition to the well-established significant (P = 0.002) increase in diabetes risk in γ as a metabolic regulator: insights from
pathway involving IRS1/2 and phosphoinositol Pro carriers. Given the prevalence of the Pro12Ala 3-kinase (PI3K), they described a pathway variant, it is arguably currently the dominant involving Cbl-associated protein (CAP), c-Cbl, genetic variant associated with diabetes. The Cbl-b, CrkII and the TC10 GTPase. The CAP gene inconsistent association studies of this variant has a PPRE in its promoter and is induced by probably reflects the importance of gene–gene and TZDs, potentially explaining the capacity of TZDs gene–environment interactions in determining the to increase insulin-stimulated glucose uptake (Ref. 68). However, Mitra et al. (Ref. 69) recently supported by a report indicating that variations knocked out CAP, c-Cbl plus Cbl-b, or CrkII using in dietary polyunsaturated fat versus saturated RNA interference in cell culture without altering fat intake influence body mass index in Ala insulin-stimulated glucose uptake, raising concerns about the biological relevance of this A much rarer, ‘gain-of-function’ mutation in pathway in insulin-induced GLUT4 translocation PPARγ – Pro115Gln – was identified in four morbidly obese people (Ref. 76). This mutation prevents phosphorylation of the serine residue at humans by regulating secretion of adipokines postion 114 and enhances transcription of PPARγ from adipose tissue (Ref. 57). Although the target genes. Although, it was suggested that capacity of adipose tissue to secrete proteins with Pro115Gln carriers had relatively little impairment endocrine activity is no longer in doubt (leptin in insulin sensitivity despite their obesity, they being the best-characterised example), many of were diabetic and formal measurements of insulin the other proteins encompassed by the term sensitivity were not undertaken. Mice were adipokine are either predominantly produced by recently generated with a homozygous Ser112Ala stromovascular cell types within adipose tissue PPARγ mutation in an effort to further explore the Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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impact of N-terminal PPARγ phosphorylation of the wild-type receptor, the mutants inhibited (Ref. 77). This mutation is similar to the Pro115Gln wild-type transcriptional activity – that is, they mutation as it prevents phosphorylation of exhibited dominant negative behaviour (Ref. 79).
Ser112 (equivalent to Ser114 in humans) and To date, all adult carriers of dominant negative enhances transcriptional activity. Surprisingly, in LBD mutations have a stereotyped form of partial contrast to the human phenotype, these mice were lipodystrophy with selective loss of limb and not obese and were protected against insulin gluteal fat. Facial fat is variably preserved, in resistance in the setting of diet-induced obesity.
contrast to the increase in facial fat noted in (Discrepancies between humans and analogous subjects with familial partial lipodystrophy pharmacology
rodent models are discussed further below.) (FPLD) due to LMNA (lamin A/C) mutations. Thelipodystrophy appears to be milder than that seen Ligand-binding-domain mutations
in typical FPLD, and is particularly difficult to More recently, several heterozygous loss-of- discern in men. All affected subjects have severe function mutations have been identified within insulin resistance, and two children, aged 3 and 7 the LBD of PPARγ (Ref. 78) (Fig. 4). In vitro years, with the Pro467Leu mutation were also characterisation of these mutations suggested hyperinsulinaemic, suggesting that insulin that: (1) the ability of the mutant proteins to resistance is a very early feature of this condition (Ref. 80). Additional features include a propensity significantly impaired; (2) the transcriptional to develop early-onset diabetes, dyslipidaemia, activity of the mutants was significantly reduced; fatty liver and hypertension. Acanthosis nigricans genomics and
and (3) when co-expressed with equal amounts and features of hyperandrogenism (polycystic γ as a metabolic regulator: insights from
Loss of function? Increased susceptibility to diabetes Loss of function? Lower BMI and reduced diabetes risk Expert Reviews in Molecular Medicine C 2005 Cambridge University Press Figure 4. Human PPARγ variants. Human genetic variants identified thus far, and their principal phenotypic
features, are indicated on a schematic representation of the domain structure of PPARγ (peroxisome-
proliferator-activated receptor γ). Dashed lines represent the PPARγ2-specific N-terminus. BMI, body mass
index; FS, (A553∆AAAiT)fs.185(stop 186).
Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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ovary syndrome) were also seen in several (Ref. 82). PPP1R3A is a key regulator of glycogen carriers. Although adipose tissue morphology was normal in the only subject in whom this was Although the human PPARG FS mutant is not examined, adipose tissue function was clearly identical to the rodent PPARγ+/− model, both disturbed in the same individual (Ref. 80). The phenotypes manifest normal insulin sensitivity on regular diets and yet render carriers susceptible clearance across subcutaneous abdominal adipose to additional metabolic insults [in the form of tissue was not seen; in fact, the clearance was very PPARγ or RXR antagonists in mice (Ref. 45) and a low both in the fasting state and postprandially.
second mutation in humans (Ref. 82)]. The ability pharmacology
Interestingly, adipose tissue lipolysis, as assessed of mutations that in isolation produce a mild by glycerol output, was also low both in the fasted phenotype, to induce severe phenotypic states in and postprandial states (Ref. 80). In addition to the presence of a ‘second hit’, whether it be partial lipodystrophy, abnormal adipose tissue environmental or genetic, might represent the sort function and fatty liver, carriers of LBD mutations of interactions responsible for complex conditions have very low plasma adiponectin levels (Ref. 80), providing yet another potential mechanism for theobserved insulin resistance. Insulin resistance is SPPARMs and dual-/pan-PPAR agonists
frequently associated with hypertension, but the The fact that PPARγ agonists appear to have two early onset and severity of hypertension seen in distinct metabolic effects – promotion of adipogenesis some carriers of PPARγ LBD mutations suggests and improved insulin sensitivity – offers the genomics and
that PPARγ might have additional effects on blood potential for these two effects to be independently pressure regulation (Ref. 79). This notion is of regulated. Rocchi et al. (Ref. 83) identified a particular interest as the principal phenotypic PPARγ ligand, N-(9-fluorenylmethyloxycarbonyl) abnormality noted in mice harbouring the rodent (FMOC)-L-leucine, capable of improving insulin sensitivity without promoting adipogenesis. This hypertension (Ref. 81). These mice had partial capacity to modulate nuclear receptor activity lipodystrophy but apparently normal insulin selectively has already been exploited in the sensitivity. Although the reasons for the striking oestrogen receptor field, where selective oestrogen differences between human and rodent phenotypes receptor modulators (SERMs) such as tamoxifen of both the gain-of-function N-terminal and loss- and raloxifene behave as anti-oestrogens in breast γ as a metabolic regulator: insights from
of-function LBD mutants remain ill understood, tissue, and as agonists of the oestrogen receptor these observations emphasise the need for in bone (Ref. 84). The tissue-specific effects of discretion when translating insights from rodent SERMs probably result from selective ligand- induced interactions between the oestrogen receptor and cofactors (co-activators and co- DNA-binding-domain mutation
repressors) (Ref. 85). When FMOC-L-leucine binds The PPARG frameshift (FS) mutant, which results to PPARγ it induces recruitment of a different in a premature stop mutation within the DNA- set of co-activators to those recruited in the binding domain (Fig. 4), differs from all the LBD presence of TZDs, suggesting that selective PPAR mutants in several respects (Ref. 82). First, it does modulators (SPPARMs) might also be a viable not exhibit in vitro dominant negative activity therapeutic option. The other approach being when co-transfected with wild-type PPARγ.
utilised in efforts aiming to separate the Second, although one of the female carriers does appear to have partial lipodystrophy, and fat increased adipogenesis is the development of mass is lower than that predicted by height and dual- and pan-PPAR agonists. As PPARα and weight in all carriers, partial lipodystrophy is not PPARδ agonists promote fat oxidation, the hope clinically apparent in several carriers of the is that dual- and/or pan-PPAR agonists might mutation. Third, two male carriers of the mutation improve insulin sensitivity while promoting had normal fasting insulin concentrations and weight loss rather than weight gain (Ref. 86).
all five insulin-resistant carriers were alsoheterozygous for a second FS premature stop Conclusions
mutation in the muscle-specific regulatory subunit PPARγ is most highly expressed in adipose tissue of phosphoprotein phosphatase 1 (PPP1R3A) where it is essential for adipogenesis. In this Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005
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regard, PPARγ2 appears to be more important 9 Daynes, R.A. and Jones, D.C. (2002) Emerging than PPARγ1. PPARγ also plays a key role in roles of PPARs in inflammation and immunity.
coordinating postprandial lipid uptake into Nat Rev Immunol 2, 748-759, PubMed: 12360213 adipocytes and release of free fatty acids in the 10 Michalik, L., Desvergne, B. and Wahli, W. (2004) fasting state for utilisation by other oxidative Peroxisome-proliferator-activated receptors and tissues such as liver and skeletal muscle. Failure cancers: complex stories. Nat Rev Cancer 4, 61- of the capacity to store excess energy in adipose tissue and/or failure to synchronise lipid 11 Issemann, I. and Green, S. (1990) Activation of a trafficking into adipose tissue with ingestion of pharmacology
food results in ectopic lipid accumulation in liver superfamily by peroxisome proliferators. Nature and skeletal muscle, and insulin resistance. The recently acknowledged capacity of adipocytes to 12 Dreyer, C. et al. (1992) Control of the peroxisomal signal the status of energy stores to other beta-oxidation pathway by a novel family of tissues such as the brain (via leptin), liver and nuclear hormone receptors. Cell 68, 879-887, skeletal muscle (possibly via adiponectin) is also subject to regulation by PPARγ. In my 13 Tontonoz, P. et al. (1994) mPPAR gamma 2: view, the available evidence strongly favours a tissue-specific regulator of an adipocyte predominant metabolic role for PPARγ within enhancer. Genes Dev 8, 1224-1234, PubMed: adipose tissue; however, tissue-selective rodent knockout models do suggest that low level 14 Fajas, L., Fruchart, J.C. and Auwerx, J. (1998) genomics and
expression of PPARγ within liver and skeletal muscle might also be biologically relevant.
mRNA subtype transcribed from an independentpromoter. FEBS Lett 438, 55-60, PubMed: 9821958 Acknowledgements and funding
15 Sundvold, H. and Lien, S. (2001) Identification of D.B.S. is supported by The Wellcome Trust, UK.
a novel peroxisome proliferator-activated The author thanks the anonymous peer reviewers receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptorRORalpha1. Biochem Biophys Res Commun 287, References
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Further reading, resources and contacts
Saltiel, A.R. and Kahn, C.R. (2001) Insulin signalling and the regulation of glucose and lipid metabolism.
Shulman, G.I. (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106, 171-176, PubMed: Stumvoll, M. and Haring, H. (2002) The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes 51, 2341-2347, PubMed: 12145143 Yki-Jarvinen, H. (2004) Thiazolidinediones. N Engl J Med 351, 1106-1118, PubMed: 15356308 pharmacology
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Features associated with this article
Figures
Figure 1. PPARγ structure and mode of gene regulation.
Figure 2. PPARγ target genes and adipocyte metabolism.
Figure 3. Thiazolidinediones and lipotoxicity.
genomics and
Table
Table 1. Gene targets of PPARγ.
Citation details for this article
David B. Savage (2005) PPARγ as a metabolic regulator: insights from genomics and pharmacology. Expert γ as a metabolic regulator: insights from
Rev. Mol. Med. Vol. 7, Issue 1, 24 January, DOI: 10.1017/S1462399405008793 Accession information: DOI: 10.1017/S1462399405008793; Vol. 7; Issue 1; 24 January 2005

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