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
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.
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.
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.
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.
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.
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.
World Health Organization. Obesity and overweight fact sheet http://www.who.int/mediacentre/factsheets/fs311/en/ (WHO, 2016).
Van Gaal, L. F., Mertens, I. L. & De Block, C. E. Mechanisms linking obesity with cardiovascular disease. Nature 444, 875–880 (2006).
Venteclef, N., Jakobsson, T., Steffensen, K. R. & Treuter, E. Metabolic nuclear receptor signaling and the inflammatory acute phase response. Trends Endocrinol. Metab. 22, 333–343 (2011).
Berrabah, W., Aumercier, P., Lefebvre, P. & Staels, B. Control of nuclear receptor activities in metabolism by post-translational modifications. FEBS Lett. 585, 1640–1650 (2011).
Pawlak, M., Lefebvre, P. & Staels, B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 62, 720–733 (2015).
Staels, B., Maes, M. & Zambon, A. Fibrates and future PPARα agonists in the treatment of cardiovascular disease. Nat. Clin. Pract. Cardiovasc. Med. 5, 542–553 (2008).
Cariou, B., Charbonnel, B. & Staels, B. Thiazolidinediones and PPARγ agonists: time for a reassessment. Trends Endocrinol. Metab. 23, 205–215 (2012).
Soccio, R. E., Chen, E. R. & Lazar, M. A. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab. 20, 573–591 (2014).
Luquet, S. et al. Peroxisome proliferator-activated receptor δ controls muscle development and oxidative capability. FASEB J. 17, 2299–2301 (2003).
Wang, Y.-X. et al. Regulation of muscle fiber type and running endurance by PPARδ. PLoS Biol. 2, e294 (2004).
Schuler, M. et al. PGC1α expression is controlled in skeletal muscles by PPARβ, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. Cell Metab. 4, 407–414 (2006).
Neels, J. G. & Grimaldi, P. A. Physiological functions of peroxisome proliferator-activated receptor β. Physiol. Rev. 94, 795–858 (2014).
Pellegrinelli, V., Carobbio, S. & Vidal-Puig, A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia 59, 1075–1088 (2016).
Medina-Gomez, G. et al. PPARγ2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. PLoS Genet. 3, e64 (2007).
Brestoff, J. R. & Artis, D. Immune regulation of metabolic homeostasis in health and disease. Cell 161, 146–160 (2015).
Trayhurn, P. Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity. Annu. Rev. Nutr. 34, 207–236 (2014).
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).
Yoneshiro, T. et al. Recruited brown adipose tissue as an antiobesity agent in humans.. J. Clin. Invest. 123, 3404–3408 (2013).
Berbée, J. F. P. et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat. Commun. 6, 6356 (2015).
Wang, Q. et al. Brown adipose tissue activation is inversely related to central obesity and metabolic parameters in adult human. PLoS ONE 10, e0123795 (2015).
Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).
Escher, P. et al. Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology 142, 4195–4202 (2001).
Ahmadian, M. et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat. Med. 19, 557–566 (2013).
Rajakumari, S. et al. EBF2 determines and maintains brown adipocyte identity. Cell Metab. 17, 562–574 (2013).
Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007). This paper highlights the role of the zinc finger protein PRDM16 in brown fat differentiation and illustrates the complex transcriptional cascade controlling adipocyte cell identity.
Tong, Y. et al. Suppression of expression of muscle-associated proteins by PPARα in brown adipose tissue. Biochem. Biophys. Res. Commun. 336, 76–83 (2005).
Hondares, E. et al. Peroxisome proliferator-activated receptor α (PPARα) induces PPARγ coactivator 1α (PGC-1α) gene expression and contributes to thermogenic activation of brown fat: involvement of PRDM16. J. Biol. Chem. 286, 43112–43122 (2011).
Barbera, M. J. et al. Peroxisome proliferator-activated receptor α activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J. Biol. Chem. 276, 1486–1493 (2001).
Rachid, T. L. et al. PPAR-α agonist elicits metabolically active brown adipocytes and weight loss in diet-induced obese mice. Cell Biochem. Funct. 33, 249–256 (2015).
Wang, Y.-X. et al. Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113, 159–170 (2003).
Pan, D., Fujimoto, M., Lopes, A. & Wang, Y.-X. Twist-1 is a PPARδ-inducible, negative-feedback regulator of PGC-1α in brown fat metabolism. Cell 137, 73–86 (2009).
Wang, F., Mullican, S. E., DiSpirito, J. R., Peed, L. C. & Lazar, M. A. Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ. Proc. Natl Acad. Sci. USA 110, 18656–18661 (2013).
Majithia, A. R. et al. Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. Proc. Natl Acad. Sci. USA 111, 13127–13132 (2014).
Step, S. E. et al. Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers. Genes Dev. 28, 1018–1028 (2014).
Lefterova, M. I., Haakonsson, A. K., Lazar, M. A. & Mandrup, S. PPARγ and the global map of adipogenesis and beyond. Trends Endocrinol. Metab. 25, 293–302 (2014).
Oger, F. et al. Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes. J. Biol. Chem. 289, 708–722 (2014).
Zhou, H. et al. Dual functions of TAF7L in adipocyte differentiation. eLife 2, e00170 (2013).
Dubois-Chevalier, J. et al. A dynamic CTCF chromatin binding landscape promotes DNA hydroxymethylation and transcriptional induction of adipocyte differentiation. Nucleic Acids Res. 42, 10943–10959 (2014).
Siersbæk, R. et al. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 7, 1443–1455 (2014).
Fujiki, K. et al. PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine. Nat. Commun. 4, 2262 (2013).
Jonker, J. W. et al. A PPARγ–FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature 485, 391–394 (2012).
Lefebvre, B. et al. Proteasomal degradation of retinoid X receptor α reprograms transcriptional activity of PPARγ in obese mice and humans. J. Clin. Invest. 120, 1454–1468 (2010).
Dutchak, P. A. et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 148, 556–567 (2012).
Pino, E., Wang, H., McDonald, M. E., Qiang, L. & Farmer, S. R. Roles for peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivators 1α and 1β in regulating response of white and brown adipocytes to hypoxia. J. Biol. Chem. 287, 18351–18358 (2012).
Gealekman, O. et al. Effect of rosiglitazone on capillary density and angiogenesis in adipose tissue of normoglycaemic humans in a randomised controlled trial. Diabetologia 55, 2794–2799 (2012).
Gealekman, O. et al. Enhanced angiogenesis in obesity and in response to PPARγ activators through adipocyte VEGF and ANGPTL4 production. Am. J. Physiol. Endocrinol. Metab. 295, E1056–E1064 (2008).
Toubal, A. et al. SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation. J. Clin. Invest. 123, 362–379 (2013). This paper shows that the transcriptional corepressor complex SMRT-GPS2 regulates proinflammatory gene expression in adipocytes and is downregulated in obesity. PPARγ activation restores its expression in obese tissue, alleviating the proinflammatory process.
Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).
Vila, I. K. et al. Immune cell Toll-like receptor 4 mediates the development of obesity- and endotoxemia-associated adipose tissue fibrosis. Cell Rep. 7, 1116–1129 (2014).
Dalmas, E. et al. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat. Med. 21, 610–618 (2015).
Guan, Y. et al. Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption. Nat. Med. 11, 861–866 (2005). Fluid retention, causing oedema in patients predisposed to T2DM and treated with thiazolidinedione, is a PPARγ-driven transcriptional process through the regulation of the expression of the amiloride-sensitive channel ENaC.
Zhang, H. et al. Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention. Proc. Natl Acad. Sci. USA 102, 9406–9411 (2005).
Kahn, S. E. et al. Rosiglitazone-associated fractures in type 2 diabetes: an analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 31, 845–851 (2008).
Giaginis, C., Tsantili-Kakoulidou, A. & Theocharis, S. Peroxisome proliferator-activated receptor-γ ligands as bone turnover modulators. Expert Opin. Investig. Drugs 16, 195–207 (2007).
Zhang, Y. et al. Growth differentiation factor 11 is a protective factor for osteoblastogenesis by targeting PPARγ. Gene 557, 209–214 (2015).
Wei, W. et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proc. Natl Acad. Sci. USA 109, 3143–3148 (2012).
Bruedigam, C. et al. A new concept underlying stem cell lineage skewing that explains the detrimental effects of thiazolidinediones on bone. Stem Cells 28, 916–927 (2010).
Wan, Y., Chong, L.-W. & Evans, R. M. PPAR-γ regulates osteoclastogenesis in mice. Nat. Med. 13, 1496–1503 (2007). Thiazolidinedione treatment increases bone fractures in women, probably resulting from decreased osteoblastogenesis from bone marrow mesenchymal stem cells, and also from increased formation of bone-resorbing osteoclasts as shown in preclinical models.
Auboeuf, D. et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-α in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes 46, 1319–1327 (1997).
Loviscach, M. et al. Distribution of peroxisome proliferator-activated receptors (PPARs) in human skeletal muscle and adipose tissue: relation to insulin action. Diabetologia 43, 304–311 (2000).
Goto, T. et al. Activation of peroxisome proliferator-activated receptor-α stimulates both differentiation and fatty acid oxidation in adipocytes. J. Lipid Res. 52, 873–884 (2011).
Guerre-Millo, M. et al. Peroxisome proliferator-activated receptor α activators improve insulin sensitivity and reduce adiposity. J. Biol. Chem. 275, 16638–16642 (2000).
Jeong, S. et al. Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice. Metabolism 53, 1284–1289 (2004).
Leuenberger, N., Pradervand, S. & Wahli, W. Sumoylated PPARα mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice. J. Clin. Invest. 119, 3138–3148 (2009).
Jeong, S. & Yoon, M. Fenofibrate inhibits adipocyte hypertrophy and insulin resistance by activating adipose PPARα in high fat diet-induced obese mice. Exp. Mol. Med. 41, 397–405 (2009).
Brun, R. P. et al. Differential activation of adipogenesis by multiple PPAR isoforms. Genes Dev. 10, 974–984 (1996).
Hiuge, A. et al. Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level. Arterioscler. Thromb. Vasc. Biol. 27, 635–641 (2007).
Tsuchida, A. et al. Peroxisome proliferator-activated receptor (PPAR)α activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARα, PPARγ, and their combination. Diabetes 54, 3358–3370 (2005).
Chinetti, G., Zawadski, C., Fruchart, J. C. & Staels, B. Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARα, PPARγ, and LXR. Biochem. Biophys. Res. Commun. 314, 151–158 (2004).
Wang, W. et al. PPARα agonist fenofibrate attenuates TNF-α-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway. Exp. Cell Res. 319, 1523–1533 (2013).
Bastie, C., Holst, D., Gaillard, D., Jehl-Pietri, C. & Grimaldi, P. A. Expression of peroxisome proliferator-activated receptor PPARδ promotes induction of PPARγ and adipocyte differentiation in 3T3C2 fibroblasts. J. Biol. Chem. 274, 21920–21925 (1999).
Bastie, C., Luquet, S., Holst, D., Jehl-Pietri, C. & Grimaldi, P. A. Alterations of peroxisome proliferator-activated receptor δ activity affect fatty acid-controlled adipose differentiation. J. Biol. Chem. 275, 38768–38773 (2000).
Hansen, J. B. et al. Peroxisome proliferator-activated receptor δ (PPARδ)-mediated regulation of preadipocyte proliferation and gene expression is dependent on cAMP signaling. J. Biol. Chem. 276, 3175–3182 (2001).
Barak, Y. et al. Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer. Proc. Natl Acad. Sci. USA 99, 303–308 (2002).
Peters, J. M. et al. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor β(δ). Mol. Cell. Biol. 20, 5119–5128 (2000).
Tanaka, T. et al. Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc. Natl Acad. Sci. USA 100, 15924–15929 (2003).
Bays, H. E. et al. MBX-8025, a novel peroxisome proliferator receptor-δ agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J. Clin. Endocrinol. Metab. 96, 2889–2897 (2011).
Sodhi, K. et al. PPARδ binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats. Int. J. Obes. 38, 456–465 (2014).
Serrano-Marco, L. et al. Activation of peroxisome proliferator-activated receptor-β/-δ (PPAR-β/-δ) ameliorates insulin signaling and reduces SOCS3 levels by inhibiting STAT3 in interleukin-6-stimulated adipocytes. Diabetes 60, 1990–1999 (2011).
Kang, K. et al. Adipocyte-derived Th2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity. Cell. Metab. 7, 485–495 (2008).
Petrovic, N. et al. Chronic peroxisome proliferator-activated receptor γ (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J. Biol. Chem. 285, 7153–7164 (2010).
Vernochet, C. et al. C/EBPα and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor γ agonists. Mol. Cell. Biol. 29, 4714–4728 (2009).
Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304–316 (2014).
Qiang, L. et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell 150, 620–632 (2012). This paper identifies that the transcriptional network regulated by PPARγ is cell-specific and conditional by post-translational modifications that regulates its ability to interact with transcriptional coregulators.
Mayoral, R. et al. Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. Mol. Metab. 4, 378–391 (2015).
Choi, J. H. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature 466, 451–456 (2010).
Banks, A. S. et al. An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. Nature 517, 391–395 (2015).
Quelle, F. W. & Sigmund, C. D. PPARγ: no SirT, no service. Circ. Res. 112, 411–414 (2013).
Glineur, C. et al. Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells. Arterioscler. Thromb. Vasc. Biol. 33, 621–628 (2013).
Loft, A. et al. Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers. Genes Dev. 29, 7–22 (2015).
Villanueva, C. J. et al. Adipose subtype-selective recruitment of TLE3 or Prdm16 by PPARγ specifies lipid storage versus thermogenic gene programs. Cell Metab. 17, 423–435 (2013).
Rachid, T. L. et al. Fenofibrate (PPARα agonist) induces beige cell formation in subcutaneous white adipose tissue from diet-induced male obese mice. Mol. Cell. Endocrinol. 402, 86–94 (2015). In this article, PPARα is identified as a promising target of obesity-related diseases due to its ability to promote beige cell formation in vivo , in HFD-fed mice.
Roberts, L. D. et al. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96–108 (2014).
Wang, L. et al. PPARα and Sirt1 mediate erythropoietin action in increasing metabolic activity and browning of white adipocytes to protect against obesity and metabolic disorders. Diabetes 62, 4122–4131 (2013). A novel function of erythropoietin in promoting oxidative metabolism and browning of WAT via a mechanism dependent on PPARα and Sirt1 is shown.
Wilcox, R., Kupfer, S., Erdmann, E. & PROactive Study investigators. Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10). Am. Heart J. 155, 712–717 (2008).
Zhang, L.-H., Kamanna, V. S., Ganji, S. H., Xiong, X.-M. & Kashyap, M. L. Pioglitazone increases apolipoprotein A-I production by directly enhancing PPRE-dependent transcription in HepG2 cells. J. Lipid Res. 51, 2211–2222 (2010).
Chinetti, G. et al. PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat. Med. 7, 53–58 (2001).
Jun, M. et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 375, 1875–1884 (2010). A systematic review and meta-analysis of fibrate actions in cardiovascular disease from 18 trials including >45,000 participants.
Bruckert, E., Labreuche, J., Deplanque, D., Touboul, P.-J. & Amarenco, P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis. J. Cardiovasc. Pharmacol. 57, 267–272 (2011).
Lee, M., Saver, J. L., Towfighi, A., Chow, J. & Ovbiagele, B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 217, 492–498 (2011).
Peters, J. M. et al. Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor α-deficient mice. J. Biol. Chem. 272, 27307–27312 (1997).
Schoonjans, K. et al. PPARα and PPARγ activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 15, 5336–5348 (1996).
Berthou, L. et al. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J. Clin. Invest. 97, 2408–2416 (1996).
Vu-Dac, N. et al. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J. Clin. Invest. 96, 741–750 (1995).
Vu-Dac, N. et al. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor α activators. J. Biol. Chem. 278, 17982–17985 (2003).
Jørgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjærg-Hansen, A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32–41 (2014).
The TG and HDL Working Group of the Exome Sequencing Project et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371, 22–31 (2014).
Colin, S. et al. Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production. Eur. Heart J. 34, 2566–2574 (2013).
Umeda, Y. et al. Inhibitory action of gemfibrozil on cholesterol absorption in rat intestine. J. Lipid Res. 42, 1214–1219 (2001).
Leibowitz, M. D. et al. Activation of PPARδ alters lipid metabolism in db/db mice. FEBS Lett. 473, 333–336 (2000).
Oliver, W. R. et al. A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. Proc. Natl Acad. Sci. USA 98, 5306–5311 (2001).
Olson, E. J., Pearce, G. L., Jones, N. P. & Sprecher, D. L. Lipid effects of peroxisome proliferator-activated receptor-δ agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 32, 2289–2294 (2012).
Akiyama, T. E. et al. Peroxisome proliferator- activated receptor β/δ regulates very low density lipoprotein production and catabolism in mice on a Western diet. J. Biol. Chem. 279, 20874–20881 (2004).
Risérus, U. et al. Activation of peroxisome proliferator-activated receptor (PPAR)δ promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 57, 332–339 (2008).
Liu, S. et al. A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. Nature 502, 550–554 (2013). This article highlights an example of liver communication with peripheral tissues to control energy homeostasis: during nocturnal feeding, PPARβ/δ-mediated lipogenesis in the liver modulates skeletal muscle fatty acid oxidation via the production of phosphatidylcholine 18:0/18:1, a PPARα ligand.
Sanderson, L. M., Boekschoten, M. V., Desvergne, B., Müller, M. & Kersten, S. Transcriptional profiling reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver. Physiol. Genomics 41, 42–52 (2010).
Barroso, E. et al. The PPARβ/δ activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1α-Lipin 1-PPARα pathway leading to increased fatty acid oxidation. Endocrinology 152, 1848–1859 (2011). In this paper, the PPARβ/δ agonist GW501516 reverses HFD-induced hypertriglyceridaemia through enhanced fatty acid oxidation and uptake via a mechanism involving amplification of the lipin 1–PGC1α–PPARα pathway.
van der Veen, J. N. et al. Reduced cholesterol absorption upon PPARδ activation coincides with decreased intestinal expression of NPC1L1. J. Lipid Res. 46, 526–534 (2005).
Vrins, C. L. J. et al. Peroxisome proliferator-activated receptor δ activation leads to increased transintestinal cholesterol efflux. J. Lipid Res. 50, 2046–2054 (2009).
Sprecher, D. L. et al. Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor δ agonist. Arterioscler. Thromb. Vasc. Biol. 27, 359–365 (2007).
Thulin, P., Glinghammar, B., Skogsberg, J., Lundell, K. & Ehrenborg, E. PPARδ increases expression of the human apolipoprotein A-II gene in human liver cells. Int. J. Mol. Med. 21, 819–824 (2008).
Chehaibi, K. et al. PPAR-β/δ activation promotes phospholipid transfer protein expression. Biochem. Pharmacol. 94, 101–108 (2015).
Lehmann, J. M. et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ). J. Biol. Chem. 270, 12953–12956 (1995). Deorphanization of PPARγ provided a molecular basis for the pharmacological, insulin sensitizing effect of thiazolidinediones.
Voight, B. F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).
Altshuler, D. et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat. Genet. 26, 76–80 (2000).
Kramer, D., Shapiro, R., Adler, A., Bush, E. & Rondinone, C. M. Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats. Metabolism 50, 1294–1300 (2001).
Ye, R. & Scherer, P. E. Adiponectin, driver or passenger on the road to insulin sensitivity? Mol. Metab. 2, 133–141 (2013).
Divakaruni, A. S. et al. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Proc. Natl Acad. Sci. USA 110, 5422–5427 (2013).
Colca, J. R. et al. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)—relationship to newly identified mitochondrial pyruvate carrier proteins. PLoS ONE 8, e61551 (2013).
Wiley, S. E., Murphy, A. N., Ross, S. A., van der Geer, P. & Dixon, J. E. MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity. Proc. Natl Acad. Sci. USA 104, 5318–5323 (2007).
Kusminski, C. M., Park, J. & Scherer, P. E. MitoNEET-mediated effects on browning of white adipose tissue. Nat. Commun. 5, 3962 (2014).
Kusminski, C. M. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat. Med. 18, 1539–1549 (2012).
Kim, H. et al. Peroxisome proliferator-activated receptor-α agonist treatment in a transgenic model of type 2 diabetes reverses the lipotoxic state and improves glucose homeostasis. Diabetes 52, 1770–1778 (2003).
Chou, C. J. et al. WY14,643, a peroxisome proliferator-activated receptor α (PPARα) agonist, improves hepatic and muscle steatosis and reverses insulin resistance in lipoatrophic A-ZIP/F-1 mice. J. Biol. Chem. 277, 24484–24489 (2002).
Larter, C. Z. et al. Peroxisome proliferator-activated receptor-α agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis. J. Gastroenterol. Hepatol. 27, 341–350 (2012).
Lalloyer, F. et al. Peroxisome proliferator-activated receptor α improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets. Diabetes 55, 1605–1613 (2006).
Black, R. N. A. et al. The peroxisome proliferator-activated receptor α agonist fenofibrate has no effect on insulin sensitivity compared to atorvastatin in type 2 diabetes mellitus; a randomised, double-blind controlled trial. J. Diabetes Complications 28, 323–327 (2014).
Lee, C.-H. et al. PPARδ regulates glucose metabolism and insulin sensitivity. Proc. Natl Acad. Sci. USA 103, 3444–3449 (2006).
Gan, Z. et al. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism. J. Clin. Invest. 123, 2564–2575 (2013).
Benetti, E. et al. High sugar intake and development of skeletal muscle insulin resistance and inflammation in mice: a protective role for PPAR- δ agonism. Mediators Inflamm. 2013, 509502 (2013).
Christodoulides, C., Dyson, P., Sprecher, D., Tsintzas, K. & Karpe, F. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man. J. Clin. Endocrinol. Metab. 94, 3594–3601 (2009).
Liu, S. et al. Role of peroxisome proliferator-activated receptor δ/β in hepatic metabolic regulation. J. Biol. Chem. 286, 1237–1247 (2011).
Bojic, L. A. et al. PPARδ activation attenuates hepatic steatosis in Ldlr−/− mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity. J. Lipid Res. 55, 1254–1266 (2014).
Qin, X. et al. Peroxisome proliferator-activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology 48, 432–441 (2008).
Ravnskjaer, K. et al. PPARδ is a fatty acid sensor that enhances mitochondrial oxidation in insulin-secreting cells and protects against fatty acid-induced dysfunction. J. Lipid Res. 51, 1370–1379 (2010).
Jiang, L., Wan, J., Ke, L., Lü, Q. & Tong, N. Activation of PPARδ promotes mitochondrial energy metabolism and decreases basal insulin secretion in palmitate-treated β-cells. Mol. Cell. Biochem. 343, 249–256 (2010).
Yang, Y. et al. Activation of PPARβ/δ protects pancreatic β cells from palmitate-induced apoptosis by upregulating the expression of GLP-1 receptor. Cell. Signal. 26, 268–278 (2014).
Daoudi, M. et al. PPARβ/δ activation induces enteroendocrine L cell GLP-1 production. Gastroenterology 140, 1564–1574 (2011).
Serrano-Marco, L. et al. The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. Diabetologia 55, 743–751 (2012).
Barroso, E. et al. PPARβ/δ ameliorates fructose-induced insulin resistance in adipocytes by preventing Nrf2 activation. Biochim. Biophys. Acta 1852, 1049–1058 (2015).
Odegaard, J. I. et al. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008).
Salvadó, L. et al. PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia 57, 2126–2135 (2014).
Coll, T. et al. Activation of peroxisome proliferator-activated receptor-δ by GW501516 prevents fatty acid-induced nuclear factor-κB activation and insulin resistance in skeletal muscle cells. Endocrinology 151, 1560–1569 (2010).
Haas, J. T., Francque, S. & Staels, B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu. Rev. Physiol. 78, 181–205 (2016).
Gavrilova, O. et al. Liver peroxisome proliferator-activated receptor γ contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J. Biol. Chem. 278, 34268–34276 (2003).
Francque, S. et al. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J. Hepatol. 63, 164–173 (2015). This article provides novel insights into the molecular mechanism of NASH in humans and implicates PPARα, whose expression decreases with progressing disease.
Lee, Y. J. et al. Nuclear receptor PPARγ-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis. Proc. Natl Acad. Sci. USA 109, 13656–13661 (2012).
Eckel-Mahan, K. L. et al. Reprogramming of the circadian clock by nutritional challenge. Cell 155, 1464–1478 (2013).
Morán-Salvador, E. et al. Role for PPARγ in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J. 25, 2538–2550 (2011).
Matsusue, K. et al. Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J. Clin. Invest. 111, 737–747 (2003).
Matsusue, K. et al. Hepatic steatosis in leptin-deficient mice is promoted by the PPARγ target gene Fsp27. Cell Metab. 7, 302–311 (2008).
Chang, B. H.-J. et al. Protection against fatty liver but normal adipogenesis in mice lacking adipose differentiation-related protein. Mol. Cell. Biol. 26, 1063–1076 (2006).
Hasenfuss, S. C. et al. Regulation of steatohepatitis and PPARγ signaling by distinct AP-1 dimers. Cell. Metab. 19, 84–95 (2014).
Escalona-Nandez, I. et al. The activation of peroxisome proliferator-activated receptor γ is regulated by Krüppel-like transcription factors 6 and 9 under steatotic conditions. Biochem. Biophys. Res. Commun. 458, 751–756 (2015).
Yamauchi, T. et al. Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes. J. Clin. Invest. 108, 1001–1013 (2001).
Li, Z., Kruijt, J. K., van der Sluis, R. J., Van Berkel, T. J. C. & Hoekstra, M. Nuclear receptor atlas of female mouse liver parenchymal, endothelial, and Kupffer cells. Physiol. Genomics 45, 268–275 (2013).
Nagy, L., Szanto, A., Szatmari, I. & Széles, L. Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response. Physiol. Rev. 92, 739–789 (2012).
Li, R. et al. CYP2J2 attenuates metabolic dysfunction in diabetic mice by reducing hepatic inflammation via the PPARγ. Am. J. Physiol. Endocrinol. Metab. 308, E270–E282 (2015).
Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).
Ratziu, V. et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial. Gastroenterology 135, 100–110 (2008).
Ratziu, V. et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51, 445–453 (2010).
Lemoine, M., Serfaty, L., Cervera, P., Capeau, J. & Ratziu, V. Hepatic molecular effects of rosiglitazone in human non-alcoholic steatohepatitis suggest long-term pro-inflammatory damage. Hepatol. Res. 44, 1241–1247 (2014).
Shafiei, M. S., Shetty, S., Scherer, P. E. & Rockey, D. C. Adiponectin regulation of stellate cell activation via PPARγ-dependent and -independent mechanisms. Am. J. Pathol. 178, 2690–2699 (2011).
Morán-Salvador, E. et al. Cell-specific PPARγ deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells. J. Hepatol. 59, 1045–1053 (2013).
Jiang, Y. et al. Histone H3K9 demethylase JMJD1A modulates hepatic stellate cells activation and liver fibrosis by epigenetically regulating peroxisome proliferator-activated receptor γ. FASEB J. 29, 1830–1841 (2015).
Jun, H.-J., Kim, J., Hoang, M.-H. & Lee, S.-J. Hepatic lipid accumulation alters global histone H3 lysine 9 and 4 trimethylation in the peroxisome proliferator-activated receptor α network. PLoS ONE 7, e44345 (2012).
Zheng, L., Lv, G., Sheng, J. & Yang, Y. Effect of miRNA-10b in regulating cellular steatosis level by targeting PPAR-α expression, a novel mechanism for the pathogenesis of NAFLD. J. Gastroenterol. Hepatol. 25, 156–163 (2010).
Loyer, X. et al. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression. Gut http://dx.doi.org/10.1136/gutjnl-2014-308883 (2015). References 178 & 179 both highlight that the epigenetic regulation of PPARα via miRNAs has a role in NAFLD pathogenesis.
Abdelmegeed, M. A. et al. PPARα expression protects male mice from high fat-induced nonalcoholic fatty liver. J. Nutr. 141, 603–610 (2011).
Pawlak, M. et al. The transrepressive activity of peroxisome proliferator-activated receptor α is necessary and sufficient to prevent liver fibrosis in mice. Hepatology 60, 1593–1606 (2014). The authors show that PPARα protects from hepatic inflammation and fibrosis independently of its action on fatty acid metabolism and steatosis in the liver.
Montagner, A. et al. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65, 1202–1214 (2016).
Ip, E., Farrell, G., Hall, P., Robertson, G. & Leclercq, I. Administration of the potent PPARα agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology 39, 1286–1296 (2004).
Ip, E. et al. Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology 38, 123–132 (2003).
Koliaki, C. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell. Metab. 21, 739–746 (2015).
Toyama, T. et al. PPARα ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats. Biochem. Biophys. Res. Commun. 324, 697–704 (2004).
Pawlak, M., Baugé, E., Lalloyer, F., Lefebvre, P. & Staels, B. Ketone body therapy protects from lipotoxicity and acute liver failure upon Pparα deficiency. Mol. Endocrinol. 29, 1134–1143 (2015).
Vernia, S. et al. The PPARα-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway. Cell Metab. 20, 512–525 (2014).
Rodríguez-Vilarrupla, A. et al. PPARα activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats. J. Hepatol. 56, 1033–1039 (2012).
Laurin, J. et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 23, 1464–1467 (1996).
Basaranoglu, M., Acbay, O. & Sonsuz, A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J. Hepatol. 31, 384 (1999).
Fernández-Miranda, C. et al. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig. Liver Dis. 40, 200–205 (2008).
Iwaisako, K. et al. Protection from liver fibrosis by a peroxisome proliferator-activated receptor δ agonist. Proc. Natl Acad. Sci. USA 109, E1369–E1376 (2012). KD3010, a new PPARβ/δ agonist displays hepatoprotective and antifibrotic properties in different models of liver injury and fibrosis, an effect not observed with another PPARβ/δ ligand, GW501516.
Nagasawa, T. et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARδ agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur. J. Pharmacol. 536, 182–191 (2006).
Wu, H.-T. et al. Pharmacological activation of peroxisome proliferator-activated receptor δ improves insulin resistance and hepatic steatosis in high fat diet-induced diabetic mice. Horm. Metab. Res. 43, 631–635 (2011).
Lee, M. Y. et al. Peroxisome proliferator-activated receptor δ agonist attenuates hepatic steatosis by anti-inflammatory mechanism. Exp. Mol. Med. 44, 578–585 (2012).
Shan, W. et al. Ligand activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression. Toxicol. Sci. 105, 418–428 (2008).
Montagner, A., Wahli, W. & Tan, N. S. Nuclear receptor peroxisome proliferator activated receptor (PPAR) β/δ in skin wound healing and cancer. Eur. J. Dermatol. 25 (Suppl. 1), 4–11 (2015).
Hellemans, K. et al. Peroxisome proliferator-activated receptor-β signaling contributes to enhanced proliferation of hepatic stellate cells. Gastroenterology 124, 184–201 (2003).
Kostadinova, R. et al. GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation. Cell Biosci. 2, 34 (2012).
Semple, R. K., Chatterjee, V. K. K. & O'Rahilly, S. PPARγ and human metabolic disease. J. Clin. Invest. 116, 581–589 (2006).
Dormandy, J. A. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366, 1279–1289 (2005). Pioglitazone treatment reduces adverse cardiovascular events in patients with advanced T2DM.
Kernan, W. N. et al. Pioglitazone after ischemic stroke or transient ischemic attack. N. Engl. J. Med. 374, 1321–1331 (2016).
Lewis, J. D. et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 314, 265–277 (2015).
Levin, D. et al. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 58, 493–504 (2015).
Tuccori, M. et al. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 352, i1541 (2016).
Whitehead, J. P. Diabetes: new conductors for the peroxisome proliferator-activated receptor γ (PPARγ) orchestra. Int. J. Biochem. Cell Biol. 43, 1071–1074 (2011).
Rosenson, R. S., Wright, R. S., Farkouh, M. & Plutzky, J. Modulating peroxisome proliferator-activated receptors for therapeutic benefit? Biology, clinical experience, and future prospects. Am. Heart J. 164, 672–680 (2012).
Henry, R. R. et al. Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 374, 126–135 (2009).
Lincoff, A. M. et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA 311, 1515–1525 (2014).
Joshi, S. R. Saroglitazar for the treatment of dyslipidemia in diabetic patients. Expert Opin. Pharmacother. 16, 597–606 (2015).
Shetty, S. R., Kumar, S., Mathur, R. P., Sharma, K. H. & Jaiswal, A. D. Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients. Indian Heart J. 67, 23–26 (2015).
Davis, T. M. E. et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 54, 280–290 (2011).
Bonds, D. E. et al. Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience. Diabetologia 55, 1641–1650 (2012).
Hennuyer, N. et al. The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis. Atherosclerosis 249, 200–208 (2016).
Ishibashi, S. et al. Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: a randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 249, 36–43 (2016).
Millar, J. S. et al. Potent and selective PPAR-α agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 29, 140–146 (2009).
Khera, A. V., Millar, J. S., Ruotolo, G., Wang, M.-D. & Rader, D. J. Potent peroxisome proliferator-activated receptor-α agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome. Eur. Heart J. 36, 3020–3022 (2015).
Gupta, R. A. et al. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-δ accelerates intestinal adenoma growth. Nat. Med. 10, 245–247 (2004).
Cymabay Therapeutics. Corporate presentation. http://content.equisolve.net/cymabay/media/9af11b3859e3b4fa04eff0f43424ffb5.pdf (2016).
He, B. K. et al. In vitro and in vivo characterizations of chiglitazar, a newly identified PPAR pan-agonist. PPAR Res. 2012, 546548 (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02121717 (2016).
Tee, J. Phase Ib clinical trial demonstrates positive finding for a new treatment for Type 2 diabetes. Diabetes Manage. 2, 16 (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01042106 (2013).
Staels, B. et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor α/δ agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58, 1941–1952 (2013).
Cariou, B., Zaïr, Y., Staels, B. & Bruckert, E. Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34, 2008–2014 (2011).
Cariou, B. et al. Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36, 2923–2930 (2013).
Ratziu, V. et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147–1159 (2016). This article describes the first multicentre trial in patients with NASH showing that elafibranor can induce resolution of the disease.
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).
B.S. is cofounder and Scientific Advisory Board president of Genfit SA. The other authors declare no competing interests.
About this article
Cite this article
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
A comprehensive review of long non-coding RNAs in the pathogenesis and development of non-alcoholic fatty liver disease
Nutrition & Metabolism (2021)
Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism
Biology of Sex Differences (2021)
Lactobacillus fermentum CQPC07 attenuates obesity, inflammation and dyslipidemia by modulating the antioxidant capacity and lipid metabolism in high-fat diet induced obese mice
Journal of Inflammation (2021)
Nature Reviews Cardiology (2021)
Galectin-1 accelerates high-fat diet-induced obesity by activation of peroxisome proliferator-activated receptor gamma (PPARγ) in mice
Cell Death & Disease (2021)