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PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD

Key Points

  • Obesity might be combated by reducing fat storage in white adipose tissue (WAT), increasing energy expenditure through adaptive thermogenesis in brown adipose tissue (BAT) and/or the browning of WAT

  • In mouse models the three peroxisome proliferator-activated receptor (PPAR) isotypes regulate adaptive thermogenesis in BAT via distinct mechanisms; PPARα and PPARγ ligands also promote WAT browning, but the relevance of these findings to human pathology is unknown

  • PPAR ligands reduce obesity-associated comorbidities by acting on fat storage capacity of WAT and fat burning in BAT and/or peripheral tissues, thereby reducing ectopic fat overload

  • PPARα and PPARγ ligands are clinically used for the treatment of dyslipidaemia and insulin resistance, respectively; in preclinical models, PPARβ/δ agonists also improve atherogenic dyslipidaemia and insulin resistance

  • Clinical trials using PPARγ agonists show favourable effects in patients with nonalcoholic steatohepatitis, but the results are so far inconclusive

  • The current challenge is to develop potent PPAR agonists without adverse effects; agonists targeting two or more PPARs that have a partial or selective gene activation pattern represent potential therapeutic approaches

Abstract

Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR agonists with improved therapeutic potential.

Main

Approximately 13% of the adult population worldwide has obesity, consequently, this disease is the most prevalent chronic metabolic disorder and one of the most important global public-health challenges1. Obesity is the result of an imbalance between energy intake and expenditure. Excess calories are initially stored in subcutaneous fat; however, when this storage capacity is overwhelmed, the altered endocrine functions of adipose tissues and the ensuing ectopic fat accumulation lead to a lipotoxic metabolic stress, which promotes low-grade inflammation and metabolic dysfunction in organs such as the liver or skeletal muscle, thereby promoting insulin resistance. The metabolic abnormalities associated with obesity predispose patients to cardiometabolic complications such as dyslipidaemia, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which put them at risk of developing cardiovascular diseases (CVD)2.

Pharmacological treatment of obesity and associated cardiometabolic comorbidities is challenging as complex metabolic and inflammatory alterations occur in several tissues. The peroxisome proliferator-activated receptors (PPARs) have emerged as integrators of inflammatory and metabolic signalling networks3. PPARs are lipid sensors that transcriptionally modulate metabolic programmes in response to nutritional inputs3. Moreover, PPARs repress proinflammatory gene expression, mostly through a transrepression mechanism3. In addition to ligand-activation, PPAR activities are also fine-tuned by post-translational modifications4. The three PPAR isotypes — PPARα (encoded by PPARA), PPARβ/δ (encoded by PPARD) and PPARγ (encoded by PPARG) — have different tissue distribution patterns and ligand specificities, which highlight their distinct functions (Table 1). PPARα function has mainly been characterized in the liver, where it regulates the adaptive response to fasting by controlling fatty acid transport, β-oxidation and ketogenesis5. PPARα is activated by fibrates, which are therapeutic agents used in the treatment of hypertriglyceridaemia6. The expression of PPARγ is highest in adipose tissues, where it regulates the acquisition and maintenance of a mature fat-storing and adipokine-secreting adipocyte phenotype7. Pharmacological activators of PPARγ include thiazolidinediones (commonly known as TZDs), such as rosiglitazone and pioglitazone, which are insulin-sensitizers used in the treatment of T2DM7,8. PPARβ/δ is highly active in skeletal muscle, where this isotype is involved in the response to exercise by regulating fatty acid catabolism and the glycolytic-to-oxidative muscle fibre switch9,10,11. Furthermore, PPARβ/δ activation improves lipid homeostasis, prevents weight gain and increases insulin sensitivity12. At present, PPARβ/δ agonists are not used clinically.

Table 1 PPAR expression, ligands, function and therapeutic potential for metabolic diseases

Fibrates and thiazolidinediones have shown promising results in reducing the CVD risk associated with T2DM6,7. However, adverse effects have restricted the use of thiazolidinediones7,8 and the low potency (in the μM range) of fibrates call for a new generation of potent and selective PPAR agonists. The development of such molecules requires a detailed knowledge of the PPAR-regulated crosstalk between adipose tissue and other tissues in the control of whole body glucose and lipid metabolism. In this Review, we summarize the role of PPARs as integrators of adipose tissue physiology and discuss new findings of their roles in obesity-associated comorbidities. Finally, we also discuss new therapeutic developments that target PPARs.

Adipose tissue and obesity

Adipose tissue consists of embryonically, topologically and functionally distinct depots. White adipose tissue (WAT) is an active endocrine organ that dynamically stores fat, whereas brown adipose tissue (BAT) converts energy into heat upon β-adrenergic stimulation or cold exposure, a process known as adaptive thermogenesis13.

In healthy conditions, fuel distribution between WAT depots and other tissues mostly involves subcutaneous WAT, which is a major and safe lipid storage organ13. During long-term caloric excess, subcutaneous WAT expandability, reflected by both hypertrophy of existing white adipocytes and increased differentiation of adipocyte progenitor and/or preadipocytes (hyperplasia) is initially sufficient to sequester triglycerides away from the liver and other tissues sensitive to triglyceride-induced lipotoxicity14. When subcutaneous WAT can no longer accommodate these excess lipids, ectopic fat accumulation occurs, which results in abdominal visceral WAT expansion and the development of peripheral insulin resistance13. In such conditions, hypoxia, fibrosis and inflammation contribute to adipocyte dysfunction and the ensuing metabolic abnormalities15,16.

BAT is also a lipid-storage depot that undergoes thermogenesis upon cold exposure and/or β-adrenergic stimulation17. Total BAT mass is thought to decline in obesity, and is inversely correlated with BMI18; whereas BAT activation might in fact decrease fat mass19. Furthermore, β-adrenergic activation of BAT reduces plasma levels of triglyceride and cholesterol in mouse models of hyperlipidaemia due to increased lipolysis and increased hepatic remnant clearance of lipoproteins20. In humans, BAT activity correlates with reduced plasma levels of triglyceride and increased HDL cholesterol21. Interestingly, thermogenic stimuli also promote the browning of WAT (known as beiging), a process that is modulated by the innate immune system and systemic factors, such as bile acids and fibroblasts growth factors (FGFs)16,20. Interfering with the adipocyte differentiation state to increase beige adipocyte numbers in rodents prevents obesity and development of T2DM22, which suggests that variations in thermogenic function of adipocytes might contribute to the regulation of body weight. Promoting the browning of WAT by pharmacological approaches might be key in the fight against obesity.

PPARs in adipose tissue physiology

BAT. PPARγ, which is expressed at similar levels in WAT and BAT23, is a key regulator of white and brown adipocyte differentiation24. In BAT, the protein products of the PPARγ target genes (such as PPARγ co-activator 1α (PGC1A) and uncoupling protein 1 (UCP1)) regulate thermogenesis and mitochondrial biogenesis (Fig. 1). In brown preadipocytes, early B cell factor-2 (EBF2) cooperates with PPARγ to regulate its DNA-binding activity and to initiate transcription of BAT-specific genes25, including PRDM16, which is a master regulator of brown adipocyte differentiation26. In the absence of EBF2, preadipocytes are present in the interscapular region, but thermogenic genes (such as UCP1) are not activated25.

Figure 1: Control of adipocyte differentiation by peroxisome proliferator-activated receptors (PPARs).
figure1

a | Differentiation of white adipose tissue (WAT). b | Differentiation of brown adipose tissue (BAT). The dietary, pharmacological and environmental cues promoting white or brown adipogenesis are indicated in red boxes. Cellular markers in mice are indicated in blue boxes. Those factors that are central to adipocyte function are indicated in green. Arrows in the green box of panel b indicate that the increase in expression of this gene leads to enhanced expression of the genes indicated. HFD, high-fat diet; PCG1α, PPARγ co-activator 1α; PDGFR, platelet derived growth factors receptor; SNS, sympathetic nervous system; TZD, thiazolidinedione.

PowerPoint slide

Expression of PPARα is approximately fourfold higher in mature BAT than in the liver23. PPARα-deficient mice, although having apparently normal BAT morphology, have thermogenesis-related disturbances, such as a marked suppression of BAT growth concurrent with a prominent decrease in fatty acid oxidative and thermogenic activities, in response to cold stress27,28. In BAT, PPARα is activated by β-adrenergic stimulated lipolysis-derived lipid ligands, and regulates the expression of genes controlling lipid oxidation and thermogenesis through a cooperative mechanism with the thermogenic factor PGC1α (Fig. 1). The PPARα–PGC1α complex regulates Ucp1 expression via a PPAR-response element in its promoter29. This regulation initiates a positive feedback loop as Pgc1a is a direct PPARα target gene28. PPARα also regulates the expression of PRDM16 in BAT, which cooperates with PPARα to potentiate Pgc1a expression28. Pharmacological PPARα activation in mice increases thermogenic gene expression and enhances energy expenditure, an effect that is believed to account for the observed weight loss30.

Data from rats indicates that PPARβ/δ expression is similar in WAT and BAT23. PPARβ/δ activation induces the expression of genes involved in fatty acid oxidation and thermogenesis in coordination with PGC1α31. PGC1α transcriptional activity is in turn antagonized by twist family BHLH transcription factor 1 (encoded by Twist1), which is also induced by PPARβ/δ32. However, the physiological role of this negative feedback regulatory mechanism is currently unclear. Indeed, activation of PPARβ/δ in BAT enhances fat oxidation and reduces fat deposition in WAT, leading to a lean phenotype upon PPARβ/δ overexpression in the adipose tissue of mice31.

WAT. PPARγ enhances insulin sensitivity, lipogenesis and adipocyte function; and PPARγ inactivation in mouse adipose tissue leads to lipodystrophy and metabolic disorders33. PPARγ variants with altered adipogenic properties are also associated with an increased risk of developing T2DM34.

PPARγ activation induces a transcriptional cascade by binding to genomic regulatory regions and inducing enhancer-RNA and associated target gene transcription35,36, which thereby controls general cell or adipocyte- specific functions37. The changes in gene expression, which involve the pro-adipogenic transcription factor, transcription-initiation factor TFIID-subunit 7-like (TAF7L)38, is preceded by chromatin remodelling that involves transcription factors such as transcriptional repressor CTCF (CTCF)39 and CCAAT/enhancer-binding protein β40. CTCF and PPARγ, by tethering of the ten-eleven translocation (commonly known as Tet) proteins in a polyADP-ribosylation-dependent manner, dynamically control DNA demethylation and gene transcription39,41. PPARγ-controlled adipocyte differentiation is, therefore, modulated by metabolic cues from lipid and glucose catabolism, which generates PPARγ agonists, polyADP ribose polymerase (PARP) substrates (such as NAD+) or Tet-activating intermediates of the Krebs cycle (αKG), in addition to acetyl-coenzyme A consuming histone modifiers that act as PPARγ co-activators.

These processes are influenced in vivo by the pathophysiological conditions to which adipocytes adapt, a process that involves the PPARγ target gene Fgf1a42. For example, in states of obesity, WAT has impaired angiogenesis, low grade chronic inflammation and is prone to fibrosis; in such hypoxic conditions, the expression of the PPARγ heterodimerization partner RXRα decreases through proteasomal degradation, altering the PPARγ-controlled transcriptome43. Altered PPARγ signalling is also seen in Fgf21-deficient mice, owing to SUMOylation-mediated inactivation of PPARγ44 and white adipocyte adaptive responses to hypoxia require both PPARγ and the hypoxia-inducible factor-1α45. Thiazolidinedione treatment promotes adipose tissue angiogenesis in mice42 and humans46, a process involving vascular endothelial growth factor and angiopoietin-like 4 (Ref. 47). The adipocyte proinflammatory response triggered by a high-fat diet (HFD) is associated with the downregulation of the transcriptional co-repressors, silencing mediator for retinoid or thyroid receptors and G-protein pathway suppressor-2; this expression can then be restored with thiazolidinediones48.

Fibrosis in WAT contributes to the metabolic alterations in obesity and/or T2DM. Fibrosis due to increased production of profibrotic transforming growth factor-β1 (TGFβ1) by macrophages49,50 limits the physical expansion of subcutaneous WAT. Blunted expansion of visceral adipose tissue due to HFD-induced fibrosis is regulated by the macrophage-polarizing interferon-regulatory factor-5 and adipocyte-produced FGF1 (Refs 42,51).

PPARγ activation in WAT can initiate positive metabolic effects by favouring WAT expansion, which leads to lipid withdrawal from metabolically active tissues and thereby alleviates lipotoxicity13. However, thiazolidinediones can induce fluid retention by acting on PPARγ in the collecting duct and altering sodium homeostasis in the kidney52,53. PPARγ agonists can also decrease bone quality and increase fracture risk in patients with T2DM54 due to an increase in marrow adipocytes. As osteoblasts and adipocytes originate from a common precursor, activation of PPARγ results in increased mesenchymal progenitor differentiation towards the adipocyte lineage, to the detriment of osteoblast formation55. Several factors can also balance the role of PPARγ in osteoblastogenesis and adipogenesis. Growth/differentiation factor 11 favours osteoblastogenesis by inhibiting PPARγ through SUMOylation56, whereas decreased PPARγ SUMOylation by FGF21 induces adipogenesis57. PPARγ also enhances osteoblast differentiation of bone-marrow-derived mesenchymal stem cells, but this differentiation is accompanied by enhanced reactive oxygen species (ROS) production and osteoblast apoptosis58. Finally, deletion of PPARγ in osteoclasts promotes osteopetrosis, which highlights that PPARγ has roles in both aspects of bone homeostasis59.

Compared with the liver, expression of PPARα is low in both human and rodent WAT, and is similar in healthy individuals and those with obesity or T2DM60,61. By contrast, in genetically or HFD-induced obesity in mice, Ppara expression is decreased62. Although such effects are yet to be reported in humans, PPARα agonists can reduce adiposity in mouse models of obesity and insulin resistance63, but this effect is not seen in female mice, which is probably the result of a negative crosstalk between PPARα and oestrogen receptors64,65. Although part of these effects might relate to increased fatty acid oxidation in the liver63,64, PPARα activation promotes both adipocyte differentiation and fatty oxidation in 3T3-L1 adipocytes and HFD-fed diabetic KK mice62,66,67. This effect results in enhanced whole-body oxygen consumption and suppression of adipocyte hypertrophy62.

Activation of PPARα in WAT also has systemic effects that might be antidiabetic and antiatherosclerotic, at least in rodents. PPARα activation induces adiponectin secretion in mice and 3T3-L1 adipocytes, an effect that is not observed in stromal vascular cells obtained from PPARα-deficient mice68. Treatment with the PPARα agonist Wy14643 (also known as pirinixic acid) of obese diabetic KKAγ mice increases expression of Adipor1 and Adipor2 in epididymal WAT and suppresses cellular and molecular obesity-related chronic inflammation69. Consistent with this finding, activation of PPARα also increases ADIPOR2 expression in primary human macrophages70. The anti-inflammatory effects of PPARα in 3T3L1 cells occurs via an AMPK-dependent upregulation of the NAD+-dependent deacetylase SIRT171. These actions in the adipocyte can, therefore, improve obesity-induced insulin resistance.

In in vitro studies, PPARβ/δ modulates preadipocyte differentiation by regulating clonal expansion and expression of adipose-related genes, including PPARγ72,73,74. Consistent with this finding, PPARβ/δ-deficient mice have a lean phenotype and reduced adiposity due to decreased adipocyte numbers75 but, paradoxically, are susceptible to HFD-induced adiposity31. Gonadal adipose stores also normalize during ageing in PPARβ/δ-deficient mice76. Conversely, the activation of PPARβ/δ protects diet-induced or genetically predisposed mouse models of obesity from weight gain by increasing energy expenditure10,31,77. However, treatment of patients with dyslipidaemia and overweight for 8 weeks with a PPARβ/δ agonist did not induce weight loss but did reduce waist circumference and plasma levels of LDL cholesterol, triglycerides and free fatty acids and increased levels of HDL cholesterol78. The metabolic function of PPARβ/δ in WAT has only been partly studied as fatty acid oxidation genes are upregulated in BAT but not in WAT31; PPARβ/δ induces a relatively low upregulation of Ucp1 in WAT compared with BAT31. In a rat model of hypertension, PPARβ/δ reverses angiotensin II-mediated adipocyte hypertrophy and dysfunction by increasing haem oxygenase-1 expression and stimulating the Wnt-canonical pathway, which leads to an increased number of smaller adipocytes with improved adiponectin secretion capability79. PPARβ/δ has anti-inflammatory properties and prevents IL-6-induced inflammation by inhibiting the signal transducer and activator of transcription-3 (STAT3)–suppressor of cytokine signalling 3 (SOCS3) pathway80. In addition, PPARβ/δ drives the polarization of resident adipose tissue macrophages (ATM) towards the anti-inflammatory M2 phenotype81.

WAT browning. PPARγ activation promotes WAT browning82,83 via a SIRT1–PPARγ–PRDM16 cascade, in which the BAT transcriptional programme is triggered by deacetylation of PPARγ and recruitment of PRDM16 to PPARγ84. This effect increases expression of BAT genes such as Ucp1 and Cidea and represses WAT-specific genes such as Resistin, thereby alleviating insulin resistance85,86. Conversely, decreased recruitment of SIRT1 to PPARγ increases PPARγ acetylation in models of HFD-induced insulin resistance and blunts the browning of WAT85. Importantly, acetylation of PPARγ might concur with phosphorylation by cyclin-dependent-like kinase 5 (CDK5) at neighbouring sites on the PPARγ protein, which results in a change in PPARγ activities from enhanced energy use (when deacetylated), adipogenesis (in nonphosphorylated, nonsumoylated states) to decreased insulin sensitivity (when phosphorylated)85,87,88. New therapies that combine the insulin sensitizing effects of blocking CDK5-mediated phosphorylation with SIRT1 activation to counterbalance the negative effect of thiazolidinediones on adiposity and promote the thermogenic programme in WAT, have been proposed89.

During the browning of WAT, expression of KLF11, a previously identified endothelial cell PPARα target gene90, is induced and cooperates with PPARγ to maintain the beige phenotype91. Conversely, selective recruitment of transducin-like enhancer of split 3 by PPARγ suppresses the expression of BAT-specific genes and impairs thermogenesis92. Consequently, PPARγ might direct the adipocyte differentiation programme, depending on its post-translational modifications and cofactor recruitment profiles that modulate its ability to activate a distinct subsets of genes.

Furthermore, PPARα overexpression in human white adipocytes leads to the acquisition of a BAT-like phenotype28. Fenofibrate treatment of HFD-fed mice triggers expression of beige cell-specific genes including Ucp1, Pgc1a, Prdm16 and Irisin in subcutaneous WAT93. Overexpression of Pgc1a in primary mouse white adipocytes results in β-aminoisobutyric acid secretion, a myokine that induces WAT browning; this mechanism is dependent on PPARα94. PPARα also cooperates with SIRT1 in erythropoetin-induced WAT beiging95. Taken together, these data indicate that PPARα has potential BAT-like phenotype-promoting activities in the pathogenesis of metabolic diseases. Although activation of PPARβ/δ in WAT is associated with increased expression of Ucp1, a role for PPARβ/δ in browning has yet to be reported.

PPARs and complications of obesity

Dyslipidaemia. Atherogenic dyslipidaemia is a major risk factor for CVD that is often present in obesity and T2DM, and is characterized by low plasma levels of HDL cholesterol and elevated levels of triglyceride-rich VLDL and small-and-dense LDL cholesterol.

The effects of PPARγ agonists, such as rosiglitazone or pioglitazone, on the risk of CVD have been evaluated in large clinical trials. Both these drugs increase plasma levels of HDL cholesterol, but substantial differences in the levels of triglycerides and LDL cholesterol have been reported8. In the PROactive trial96, pioglitazone reduced major adverse cardiovascular events in patients with T2DM, which was a secondary end point in this study. This result was accompanied by lowered levels of triglycerides and increased HDL-cholesterol levels. Pioglitazone can also induce the production of apolipoprotein (Apo) A1 rich-HDL particles and stimulates reverse cholesterol transport by acting on macrophages, as well as inhibits monocyte adhesion to endothelial cells and macrophage activation7. Increased ApoA1 expression might be due to partial activation of PPARα by pioglitazone97. PPARγ promotes cholesterol efflux from macrophages via an indirect pathway involving the Liver X Receptor α (encoded by LXRA) and its target gene ABCA1 (Ref. 98). By contrast, rosiglitazone, which does not activate PPARα, seems to have a neutral effect on cardiovascular events in patients with T2DM and has less favourable effects than pioglitazone on lipoprotein metabolism7.

Fibrates are PPARα agonists used in the treatment of hypertriglyceridaemia to decrease levels of triglycerides, but also elevate levels of HDL cholesterol6. In a meta- analysis, fibrate treatment seemed to reduce the incidence of CVD events in patients with hypertriglyceridaemia or combined dyslipidaemia99,100,101. In mice, PPARα controls lipid homeostasis by regulating the expression of genes involved in fatty acid transport and oxidation, hence lowering plasma levels of triglycerides102. Hepatic PPARα activity controls lipoprotein metabolism through the regulation of apolipoprotein expression, and functional PPAR-response elements have been identified in the promoters of the human LPL, APOA5, APOA1 and APOA2 genes103,104,105,106. In addition to stimulating LPL activity, PPARα agonists also decrease expression of APOC3, a causal CVD risk factor as shown through Mendelian randomization studies and a loss-of-function mutation analysis107,108. This effect thereby enhances lipolysis of triglyceride-rich lipoproteins. Intestinal PPARα activation reduces cholesterol esterification and absorption and increases HDL-cholesterol secretion by inducing APOA1 and ABCA1 (Refs 109,110). In macrophages, PPARα activation enhances ABCA1-driven reverse cholesterol transport98.

PPARβ/δ agonists increase plasma levels of HDL cholesterol, and reduce levels of LDL cholesterol, triglycerides and free fatty acids in different rodent and primate models, as well as in humans with dyslipidaemia78,111,112,113. PPARβ/δ-deficient mice fed a HFD have high plasma levels of triglycerides due to elevated hepatic VLDL production and reduced LPL-mediated catabolism114. PPARβ/δ also regulates VLDL–ApoB production and clearance in humans113,115. PPARβ/δ regulates lipid homeostasis via a combined effect on several organs including the liver, adipose tissue and skeletal muscle11,31,116. Agonism of PPARβ/δ can enhance lipid catabolism in skeletal muscle and adipose tissue10,31,77. Consistent with the triglyceride-lowering action of PPARβ/δ in vivo, gene expression profiling indicates that hepatic PPARβ/δ controls the expression of genes involved in lipoprotein metabolism (VldlR, ApoA5, ApoA4, ApoC1)117. Interestingly, PPARβ/δ also induces hepatic expression levels of PPARα target genes that are involved in fatty acid oxidation via a mechanism that involves the lipin 1–PGC1α–PPARα signalling system118. PPARβ/δ activation increases PPARA expression and PPARα DNA-binding activity, and enhances hepatic levels of the endogenous PPARα ligand 16:0/18:1-phosphatidylcholine118, which is consistent with the partial overlap of PPARα and PPARβ/δ target genes in mouse liver117. In addition, intestinal PPARβ/δ activation decreases cholesterol absorption through downregulation of Niemann-Pick C1-like 1, which is involved in cholesterol absorption119, and increases reverse cholesterol transport through the stimulation of transintestinal cholesterol efflux120. Finally, PPARβ/δ increases levels of HDL cholesterol and enhances reverse cholesterol transport in primate and human macrophages via the ABCA1 pathway112,121, as well as increases APOA2 expression in human hepatocytes122 and phospholipid transfer protein (PLTP), an HDL remodelling enzyme that promotes preβ-HDL formation123. These mechanisms (that is, reverse cholesterol transport, APOA2 and PLTP) are important for HDL formation.

T2DM. Hyperglycaemia owing to liver and peripheral tissue insulin resistance and pancreatic β-cell failure gives rise to T2DM. Thiazolidinediones are insulin sensitizers that were widely used for treating T2DM until safety concerns restricted their use7,8. Thiazolidinediones increase insulin action to stimulate skeletal muscle glucose disposal and inhibit liver glucose output. In addition, thiazolidinediones preserve pancreatic β-cell function and thereby prevent the progression of prediabetes to T2DM. Thiazolidinediones seem to mediate most of their effects through binding to PPARγ124. The systemic metabolic effects of PPARγ have been investigated mostly through the generation of tissue-specific PPARγ-deficient mice. Genome-wide association studies and PPARγ variant analysis also revealed the contribution of the PPARγ gene to the development of T2DM in humans34,125,126.

Adipose tissue is the primary target for PPARγ agonists in the control of lipid metabolism, glucose homeostasis and adipokine secretion7, and PPARγ agonists can promote subcutaneous fat mass expansion and lipid storage capacity. Free fatty acids in the circulation and peripheral tissues are redirected, transformed and stored as triglycerides in adipose tissue. Reversing lipotoxicity in the liver and peripheral tissues restores metabolic function in these tissues, promotes glucose use and improves insulin sensitivity7.

In muscle, PPARγ agonists increase glucose utilization via upregulation of expression of GLUT1 (Ref. 127). PPARγ induction of adipokines, such as adiponectin, sensitizes the liver and skeletal muscles to insulin128. However, investigators have suggested that some metabolic effects of thiazolidinediones might occur independently of PPARγ, via binding to the mitochondrial target of thiazolidinedione (that is, mitochondrial pyruvate carrier 1 and mitochondrial pyruvate carrier 2); this inhibition leads to improved glucose uptake129. Binding of structural analogues of pioglitazone, which have a weak affinity for PPARγ, to mitochondrial target of thiazolidinedione improves insulin sensitivity and favours the development of BAT in mice130. Pioglitazone also binds to a mitochondrial protein (CDGSH iron-sulfur domain-containing protein 1; commonly known as MitoNEET), containing the amino acid sequence Asn-Glu-Glu-Thr, which controls mitochondrial respiratory rate131 and favours expansion of WAT, thus improving lipid and glucose homeostasis132,133.

In rodents models of T2DM, PPARα agonists improve glucose homeostasis by enhancing insulin sensitivity in adipose tissue and muscle, and by decreasing lipotoxicity, which is probably the result of increased β-oxidation63,134,135,136. These positive metabolic effects are accompanied by weight loss and/or reduced liver steatosis63,134,135,136. In addition, PPARα agonists can slow the progression of T2DM by preserving pancreatic β-cell function137. However, fibrates do not seen to improve glucose homeostasis in humans138.

PPARβ/δ agonists also improve glucose handling and insulin sensitivity in mouse models of T2DM77,139, which is the result of changing the expression of glucose and fatty acid utilization genes in skeletal muscle, adipose tissue and liver. PPARβ/δ agonists enhance energy expenditure by stimulating fatty acid catabolism in muscle10,77 and adipose tissue31 and by increasing thermogenesis in BAT31. As a consequence, the fatty acid flux is moved from WAT and other peripheral tissues to muscle and adipose tissue and thereby alleviates the fat burden responsible for insulin resistance10,31. In addition, PPARβ/δ induces a muscle fibre type shift toward oxidative metabolism9,10,11, via a mechanism involving muscle microRNA and oestrogen-related receptor γ regulatory networks140. Conversely, ablation of PPARβ/δ in skeletal muscle results in reduced oxidative capacity, which precedes the appearance of age-dependent obesity and T2DM11. The PPARβ/δ-induced fibre type switch is similar to that occurring during physical exercise9,10, which indicates common regulatory mechanisms between exercise and PPARβ/δ in muscle. Furthermore, the protective role of PPARβ/δ in fructose-induced insulin resistance might involve increased Fgf21 expression in muscle cells141. PPARβ/δ agonist treatment can also increase plasma levels of FGF21 in humans142. Interestingly, PPARβ/δ can also indirectly regulate skeletal muscle fatty acid use by modifying hepatic gene expression. For example, during the dark phase, when mice are active, hepatic PPARβ/δ induces synthesis and secretion of 18:0/18:1-phosphatidylcholine, which acts as a specific PPARα activator to induce fatty acid use in skeletal muscle116.

PPARβ/δ reduces gluconeogenesis and enhances glucose uptake, glycogen storage, glycolysis, the pentose phosphate pathway117,139,143 and lipogenesis in the liver139,143. Despite de novo production of lipids by lipogenesis, livers are protected from lipotoxicity as lipids are believed to be mainly oxidized in the skeletal muscle139. However, some investigators have associated improved PPARβ/δ agonist-induced insulin sensitivity to liver activation of fatty acid oxidation118,144, inhibition of lipogenesis owing to reduced proteolytic processing of sterol regulatory element-binding protein 1C (SREBP1C) to an active form by the PPARβ/δ target gene Insig-1 (Refs 144,145) and prevention of hepatic lipid accumulation144,145. However, these differences might be related to the use of different animal models and metabolic conditions or the use of specific PPARβ/δ agonists.

In mice, activation of PPARβ/δ restores pancreatic insulin secretion in the ob/ob model of obesity77; and in β cells, it promotes mitochondrial fatty oxidation and glucose-induced insulin secretion146,147. In addition, PPARβ/δ activation stimulates glucagon-like peptide 1 (GLP1) receptor expression in β cells and thereby enhances the protective activity of GLP1 on lipotoxicity-mediated apoptosis148,149. Furthermore, PPARβ/δ enhances glucose-induced GLP1 release from intestinal L cells and upregulates proglucagon gene transcription149.

The transcriptional profiling of livers from PPARβ/δ- deficient mice has enabled the identification of an anti-inflammatory activity117, which might be of potential benefit in the chronic and low-grade inflammatory state of T2DM. PPARβ/δ activation inhibits IL-6-induced inflammation and insulin resistance by interfering with the STAT3–SOCS3 pathway in mouse liver and human hepatoma cells150. Similar anti-inflammatory mechanisms can alleviate IL-6-mediated adipocyte glucose uptake in mice80. Conversely, adipose tissue inflammation and glucose intolerance are exacerbated in fructose-fed PPARβ/δ-deficient mice151. These effects are the result of increased expression of nuclear factor E2-related factor 2 in WAT, which is normally inhibited by PPARβ/δ activation151. PPARβ/δ also drives the alternative polarization of resident macrophages, Kupffer cells and ATM, thereby decreasing the inflammatory response81,152. Consistent with this notion, PPARβ/δ deletion in macrophages or myeloid cells abrogates the alternative polarization of resident macrophages and triggers glucose intolerance, insulin resistance and hepatosteatosis in HFD-fed mice81,152. In addition, inhibition of lipid-mediated inflammation and endoplasmic reticulum stress upon PPARβ/δ activation prevents insulin resistance in the skeletal muscle via activation of the AMPK signalling pathway153. Finally, inactivation of nuclear factor-κB is also thought to mediate the anti-inflammatory mode of action of PPARβ/δ in mouse and human skeletal muscle cells and whole mice skeletal muscle tissue141,154.

NAFLD and NASH. Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that progresses from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis, which predisposes patients to cirrhosis155. The progression of steatosis to NASH results in a disease state characterized by inflammation and hepatocellular damage that results in hepatic stellate cells switching towards a myofibroblastic profibrogenic phenotype (Fig. 2)155. Optimal therapy for NAFLD should, therefore, target inflammation and hepatocellular damage to prevent fibrosis. No approved treatment for NASH currently exists, but as PPAR agonists improve metabolic dysfunction, inflammation and oxidative stress associated with these liver diseases, these drugs have received attention from the NAFLD and NASH research community.

Figure 2: Peroxisome proliferator-activated receptors (PPARs) in hepatic lipid metabolism and nonalcoholic fatty liver disease (NAFLD).
figure2

The function of PPARs in fatty acid metabolism, inflammation and fibrogenesis in different hepatic cell types and adipose tissue. Factors and genes that are central to the functions indicated in blue boxes and regulated by PPARs are indicated in green boxes. BAT, brown adipose tissue; FFA, free fatty acids; ROS, reactive oxygen species; T2DM, type 2 diabetes mellitus; TG, triglycerides; WAT, white adipose tissue.

PowerPoint slide

Expression of PPARγ in the liver is very low under healthy conditions, but increases as steatosis develops in rodents156; this effect is not seen in humans157. C3H mice, which do not express PPARγ in the liver, are resistant to HFD-induced steatosis158. Importantly, PPARγ activity acquires a circadian rhythmicity in the liver of HFD-fed mice, thereby contributing to observed transcriptomic and metabolomic perturbations in these metabolically-challenged mice159. Conversely, ob/ob mice with a hepatocyte-specific deletion of PPARγ are resistant to steatosis160, but develop pronounced insulin resistance and hyperglycaemia161. The prosteatotic activity of hepatic PPARγ is due to the upregulation of genes involved in lipogenesis (such as Acc1, Cd36 and Scd1), triglyceride synthesis (Mogat1) and lipid droplet formation (Fsp27, Plin2 and Cidea)158,162,163. In HFD-induced steatosis, sustained expression of PPARγ is mediated through specific activator protein-1 (AP-1) heterodimers, with JunD having an important role in maintaining the prosteatotic activity of PPARγ164. A role for KLF6 and KLF9 in inducing PPARγ expression under steatotic conditions has also been proposed165. Finally, pharmacological inhibition of PPARγ or its heterodimerization partner RXR ameliorates fatty liver166.

Although the expression of PPARγ1 and PPARγ2 isoforms is low in mouse Kupffer cells167, thiazolidinediones exert systemic anti-inflammatory activities168. In diabetic db/db mice, generation of PPARγ ligands from arachidonic acid by expression of the hepatic enzyme cytochrome P450 2J2 ameliorates inflammation and metabolic parameters and these effects are abrogated by a PPARγ antagonist169. In humans, pioglitazone, which also has PPARα activity, can improve liver lobular inflammation and ballooning, which leads to the improvement of NASH in some patients treated with this drug, and also improves liver steatosis170. By contrast, treatment with the selective PPARγ agonist rosiglitazone can improve steatosis, but did not improve liver inflammation and fibrosis in the FLIRT trial171,172,173.

The phenotypic conversion of hepatic stellate cells to extracellular-matrix-producing myofibroblasts is induced by hormonal signals such as TGFβ1. Thiazolidinediones suppress this profibrotic response in an adiponectin-dependent manner174, and PPARγ deletion in mouse hepatic stellate cells and adipocytes exacerbates chemical-induced fibrosis175. PPARγ expression is epigenetically suppressed by the H3K9 methylase JMJD1a in chemically-induced fibrosis176. However, treatment of patients with NASH using rosiglitazone or pioglitazone did not seem to improve liver fibrosis170,173. This lack of effect was probably the result of species-specific differences, as some preclinical models imperfectly mimic the human disease, or of the short duration of the clinical trials.

PPARα is one of the most abundantly expressed nuclear receptors in the liver, but mRNA transcripts for this gene progressively decrease as NASH progresses in humans157. Epigenetic mechanisms might be involved in this downregulation as H3K9me3 and H3K4me3 signatures are altered in the mouse hepatic Ppara promoter in a mouse model of NASH177. Post-transcriptional silencing of PPARα also occurs via miRNA-10b in hepatocyte LO2 cells and by miRNA-21, whose expression is increased in mice and humans with NASH178,179. Whole-body and hepatocyte-specific PPARα-deficient mice develop aggravated liver steatohepatitis upon HFD and methionine and choline-deficient diet feeding180,181,182, and in preclinical models, pharmacological activation of PPARα has preventive and curative effects on NASH183,184. Activation of parenchymal cell PPARα improves hepatic lipid metabolism by increasing ω-oxidation as well as peroxisomal and mitochondrial β-oxidation, which leads to enhanced hepatic transport, oxidation and metabolism of adipose tissue lipolysis-generated free fatty acids, which thereby improves metabolic flexibility during fed-fasting transition states5,182.

Mitochondrial function is also impaired in the livers of patients with NASH, who have increased hepatic oxidative stress, oxidative DNA damage and mitochondrial leaking activity185. PPARα has hepatoprotective actions via hydrogen peroxide detoxification and decreases hepatic ROS pools by upregulating catalase expression in thioacetamide-induced liver fibrosis in rats186. Induction of ketogenesis leads to PPARα-induced decreases in hepatic lipid peroxidation and ROS production due to the neutralization of toxic fatty acid-derived aldehydes by β-hydroxybutyrate187. Activation of the JNK pathway, which drives HFD-induced insulin resistance, also decreases PPARα target gene expression in the liver owing to increased expression of Ncor1 and Nrip1 co-repressors via AP-1 binding sites in their promoters188. In accordance with this finding, hepatic JNK deficiency in HFD-fed mice leads to increased expression of Fgf21 and elevated plasma levels of FGF21, which improves systemic metabolism188. In preclinical studies, hepatic anti-inflammatory and antifibrotic effects of PPARα agonism resulted in reduced numbers of activated macrophages, decreased levels of IL-1β and IL-6 and improved histological evidence of liver dysfunction, endothelial function and haemodynamics via reduced cyclooxygenase-1 (COX-1) protein levels181,184,189. The anti-inflammatory and antifibrotic properties of PPARα have been associated with its ability to directly repress the transcription of inflammation and fibrosis gene clusters, independent of its transactivation effects on fatty acid oxidation genes and liver steatosis181. In pilot clinical studies with fenofibrate and gemfibrozil in patients with NASH, plasma levels of alanine transaminase, aspartate transaminase and γ-glutamyl transpeptidase were reduced190,191,192. However, direct assessment of the effect of PPARα agonists on NASH and fibrosis has not yet been completed, therefore, novel synthetic PPAR agonists are currently in development.

PPARβ/δ is expressed in hepatocytes, Kupffer cells and stellate cells193. In several mouse studies, long-term activation of PPARβ/δ can improve hepatic steatosis by activating fatty acid β-oxidation in different diet-induced models of steatohepatitis (NASH, obesity and insulin resistance)144,194,195 and by reducing lipogenesis144,145. However, in some studies lipogenesis and hepatic levels of triglycerides can increase upon PPARβ/δ activation without hepatoxicity139,143. Administration of PPARβ/δ ligands also reduces expression of inflammatory genes such as Tnfa, Il1b and Ccl2/Mcp1 (Refs 144,194,196,197), as well as markers of endoplasmic reticulum stress in hepatocytes144. PPARβ/δ in Kupffer cells also contributes to hepato-protection; deletion of this isotype in bone marrow progenitors predisposes HFD-fed mice to hepatic steatosis with increased lipogenesis and decreased oxidative metabolism152. Interestingly, improvement of hepatosteatosis or NASH by PPARβ/δ agonists is associated with improved hyperglycaemia143,196 or hepatic insulin resistance144,195.

PPARβ/δ has an important role in tissue repair and in wound healing, which might be of relevance to liver disease198. However, the antifibrotic effects of PPARβ/δ in liver are currently a matter of debate with different results presented by investigators using synthetic agonists (GW501516, GW610742, L-165041 or KD3010) and PPARβ/δ-deficient mice193,197,199,200. Interestingly, some of the reported antifibrotic effects of PPARβ/δ are mediated independently of modulation of fibrogenic properties of hepatic stellate cells193,197. In the former case, differences in the potency, tissue distribution, mode of action (recruitment of cofactors), compound dose, metabolism of the ligands and/or phenotypic assessment of disease state might explain these different effects, but further investigations are needed.

Finally, in clinical studies that included patients with dyslipidaemia and abdominal obesity, defined as BMI >27 kg/m2 and waist girth >95 cm, or those who were overweight with mixed dyslipidaemia, characterized by low levels of HDL cholesterol and high levels of LDL cholesterol and triglycerides, putatively at high risk of NAFLD, showed a reduction of hepatic fat content upon treatment with PPARβ/δ agonists78,115. This finding was also associated with improved plasma markers of liver function (such as γ-glutamyl transpeptidase and alkaline phosphatase)78,115. PPARβ/δ activation also reduces the number of patients meeting criteria of the metabolic syndrome78.

Future therapeutic directions

Currently used agonists are only weakly potent (as is the case for PPARα) and/or are associated with adverse effects (such as in PPARγ). In the past decade, compounds have been developed with combined effects, such as dual PPAR agonists (for example, PPARα/γ, PPARα/β(δ) and PPARβ(δ)/γ) and pan-PPAR agonists or selective modulators, displaying selective tissue and gene-specific activities, aimed at preventing adverse effects.

The role of PPARγ in glucose metabolism and insulin sensitivity is clearly established but an unmet need for insulin sensitizers still exists. This favourable effect essentially stems from increased lipid storage activity, a result of the proadipogenic activity of PPARγ2. Heterozygous PPARγ-deficient mice and human carriers of the Pro12Ala mutant of PPARγ have altered insulin resistance201. However, whether PPARγ antagonists, agonists or partial agonists, alone or in combination with other treatments, should be sought is still unclear. Notwithstanding protective cardiovascular effects against myocardial infarction and stroke of pioglitazone in patients with T2DM202 or with insulin resistance203, rosiglitazone (in the European Union) and pioglitazone (France) have been withdrawn from the market in Europe, owing to controversial reports of increased risk of myocardial infarction (rosiglitazone) and reported bladder cancer (pioglitazone)24,204,205,206. Further understanding of the basic mechanisms that regulate PPARγ transcriptional activity, and the modulation thereof by small molecules, has enabled the development of selective PPARγ activators without adverse effects. Notably, the finding that CDK5, which is upregulated in obesity, can phosphorylate PPARγ resulting in increased expression of genes associated with insulin resistance has led to the discovery of PPARγ-phosphorylation inhibitors, which have limited adverse effects207. Alternatively, targeting of both PPARα and PPARγ has led to the development of dual PPARα/γ agonists (known as the glitazars)208. However, despite encouraging preliminary phase II results209, aleglitazar did not improve cardiovascular outcomes in a phase III trial and further development was halted210. Saroglitazar, a novel PPARα/γ agonist currently used in India, has few reported adverse effects, and improves glycaemia and the lipid profile211,212.

Current PPARα agonists have some efficacy in reducing cardiovascular risk in patients with T2DM who also have atherosclerotic dyslipidaemia6. PPARα agonists have few adverse effects, but do generally increase plasma levels of homocysteine and creatinine, which are pharmacodynamic markers rather than indicators of cardiovascular risk or renal dysfunction as their levels rapidly return to normal upon stopping drug treatment213,214. Pemafibrate (also known as K-877) is a novel selective PPARα modulator, which has lipid lowering and antiatherosclerotic activities in preclinical models: specifically, the human ApoE2 knockin and human APOA1 transgenic mice fed a western diet215. Furthermore, in a phase II clinical trial including patients with dyslipidaemia, pemafibrate improved plasma levels of triglycerides, remnant lipoprotein cholesterol and HDL cholesterol compared with fenofibrate216. LY518674, another potent and selective PPARα agonist enhances cholesterol efflux capacity in patients with the metabolic syndrome treated with the drug for 8 weeks, but without changing levels of plasma ApoA1 and HDL cholesterol217,218.

PPARβ/δ is also a target for management of the different components of the metabolic syndrome such as dyslipidaemia, T2DM and NAFLD or NASH. Although the development of the PPARβ/δ agonist GW501516 was halted due to the risk of preclinical adenocarcinoma219, in phase IIa clinical trials favourable effects were seen on lipid metabolism, energy expenditure and inflammation115 prompting further development of other PPARβ/δ agonists. One such agonist (known as MBX-8025) improves mixed dyslipidaemia and decreases the proportion of patients who meet the criteria for the metabolic syndrome, as well as plasma markers of liver function such as γ-glutamyl transpeptidase and alkaline phosphatase78. In a phase II study of MBX-8025 in patients with genetically confirmed homozygous familial hypercholesterolaemia, also treated with ezetimibe and maximum statin therapy, a significant reduction in LDL-cholesterol levels was seen220. Interestingly, MBX-8025 treatment also increased expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), which suggests this drug might be used as a cotherapy with PCSK9 inhibitors to strengthen the lowering effects on LDL cholesterol levels. Preliminary results from an ongoing phase II trial in patients with primary biliary cholangitis shows an improvement in the pathological levels of alkaline phosphatase and γ-glutamyl transpeptidase, which might reflect an effect of PPARβ/δ on tissue repair and liver scarring220.

Molecules that combine PPAR isotype agonism are promising treatments of several features of the metabolic syndrome and NASH. For example, a pan-PPAR agonist improves glucose and lipid homeostasis in patients with T2DM221 and a phase III study using this agonist has begun in China222. An agonist targeting PPARβ/δ and PPARγ (which predominantly has PPARβ/δ activity), has shown antidiabetic activity and improved dyslipidaemia without increasing weight gain in preclinical and phase I studies223. A dual PPARα/γ agonist with antihyperglycaemic, trigyceride-lowering and HDL-cholesterol-rising activities, is currently being tested in a phase I clinical trial224. In preclinical studies, the dual PPARα/β(δ) agonist elafibranor (GFT505) has a broad spectrum of antisteatotic, anti-inflammatory and antifibrotic effects in rodent models225. In a phase IIa clinical trial, elafibranor could lower levels of alanine transaminase, γ-glutamyl transpeptidase, alkaline phosphatase, triglycerides and remnant cholesterol and increase HDL cholesterol in patients with abdominal obesity who had dyslipidaemia or prediabetes226,227. Moreover, elafibranor improves hepatic and peripheral insulin sensitivity as shown by hyperinsulinaemic euglycaemic clamps in patients with prediabetes227. Finally, in results from a multicentre phase IIb clinical trial in patients with NASH, elafibranor reversed NASH without worsening of fibrosis, while improving lipid and glucose metabolism228.

Conclusions

The potential of PPAR agonists is well-established in therapeutic areas related to lipid and glucose metabolism and inflammation such as T2DM, obesity, dyslipidaemia and NAFLD and/or NASH. Despite beneficial effects, some PPAR agonists have adverse effects or limited potency. During the past few years, knowledge on the physiological functions and mode of action of PPARs has considerably increased, which should help the development of new PPAR-targeting therapies. Future therapeutic developments lie in the field of dual or pan-PPAR modulators with partial or selective activation profiles as they are associated with reduced adverse effects and optimal efficacy.

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Acknowledgements

B.S. is a member of the Institut Universitaire de France. Work in the authors' laboratories has been supported by grants from European Genomic Institute for Diabetes (ANR-10-LABX-46), the European Commission (RESOLVE contract FP7-305707 and FISHMED contract FP7-316125), Fondation de France, Fondation pour la Recherche Médicale (DEQ20150331724) and National Science Center Program, Poland (SONATA 2014/15/D/NZ5/03421).

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B.G., M.P. and P.L. researched data for the article. All authors made substantial contributions to discussion of the content and wrote, edited and reviewed the manuscript before submission.

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Correspondence to Bart Staels.

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B.S. is cofounder and Scientific Advisory Board president of Genfit SA. The other authors declare no competing interests.

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Gross, B., Pawlak, M., Lefebvre, P. et al. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol 13, 36–49 (2017). https://doi.org/10.1038/nrendo.2016.135

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