Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD

Key Points

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

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

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

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

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

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

Abstract

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

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Control of adipocyte differentiation by peroxisome proliferator-activated receptors (PPARs).
Figure 2: Peroxisome proliferator-activated receptors (PPARs) in hepatic lipid metabolism and nonalcoholic fatty liver disease (NAFLD).

Similar content being viewed by others

References

  1. World Health Organization. Obesity and overweight fact sheet http://www.who.int/mediacentre/factsheets/fs311/en/ (WHO, 2016).

  2. Van Gaal, L. F., Mertens, I. L. & De Block, C. E. Mechanisms linking obesity with cardiovascular disease. Nature 444, 875–880 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. 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).

    Article  CAS  PubMed  Google Scholar 

  7. Cariou, B., Charbonnel, B. & Staels, B. Thiazolidinediones and PPARγ agonists: time for a reassessment. Trends Endocrinol. Metab. 23, 205–215 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Luquet, S. et al. Peroxisome proliferator-activated receptor δ controls muscle development and oxidative capability. FASEB J. 17, 2299–2301 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, Y.-X. et al. Regulation of muscle fiber type and running endurance by PPARδ. PLoS Biol. 2, e294 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. Neels, J. G. & Grimaldi, P. A. Physiological functions of peroxisome proliferator-activated receptor β. Physiol. Rev. 94, 795–858 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Pellegrinelli, V., Carobbio, S. & Vidal-Puig, A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia 59, 1075–1088 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Medina-Gomez, G. et al. PPARγ2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. PLoS Genet. 3, e64 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brestoff, J. R. & Artis, D. Immune regulation of metabolic homeostasis in health and disease. Cell 161, 146–160 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Trayhurn, P. Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity. Annu. Rev. Nutr. 34, 207–236 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Yoneshiro, T. et al. Recruited brown adipose tissue as an antiobesity agent in humans.. J. Clin. Invest. 123, 3404–3408 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Berbée, J. F. P. et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat. Commun. 6, 6356 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Escher, P. et al. Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology 142, 4195–4202 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Ahmadian, M. et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat. Med. 19, 557–566 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Rajakumari, S. et al. EBF2 determines and maintains brown adipocyte identity. Cell Metab. 17, 562–574 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, Y.-X. et al. Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113, 159–170 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Zhou, H. et al. Dual functions of TAF7L in adipocyte differentiation. eLife 2, e00170 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Siersbæk, R. et al. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 7, 1443–1455 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Fujiki, K. et al. PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine. Nat. Commun. 4, 2262 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Jonker, J. W. et al. A PPARγ–FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature 485, 391–394 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dutchak, P. A. et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 148, 556–567 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

  49. Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Dalmas, E. et al. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat. Med. 21, 610–618 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. 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.

    Article  CAS  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    Article  CAS  PubMed  Google Scholar 

  55. 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).

    Article  CAS  PubMed  Google Scholar 

  56. Zhang, Y. et al. Growth differentiation factor 11 is a protective factor for osteoblastogenesis by targeting PPARγ. Gene 557, 209–214 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  58. 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).

    CAS  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Guerre-Millo, M. et al. Peroxisome proliferator-activated receptor α activators improve insulin sensitivity and reduce adiposity. J. Biol. Chem. 275, 16638–16642 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. 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).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Brun, R. P. et al. Differential activation of adipogenesis by multiple PPAR isoforms. Genes Dev. 10, 974–984 (1996).

    Article  CAS  PubMed  Google Scholar 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. 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).

    Article  CAS  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  Google Scholar 

  71. 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).

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

  73. 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).

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  Google Scholar 

  75. 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).

    Article  CAS  PubMed  Google Scholar 

  76. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  Google Scholar 

  80. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kang, K. et al. Adipocyte-derived Th2 cytokines and myeloid PPARδ regulate macrophage polarization and insulin sensitivity. Cell. Metab. 7, 485–495 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 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).

    Article  CAS  PubMed  Google Scholar 

  83. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Choi, J. H. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature 466, 451–456 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Banks, A. S. et al. An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. Nature 517, 391–395 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Quelle, F. W. & Sigmund, C. D. PPARγ: no SirT, no service. Circ. Res. 112, 411–414 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    Article  CAS  PubMed  Google Scholar 

  91. Loft, A. et al. Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers. Genes Dev. 29, 7–22 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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.

    Article  CAS  PubMed  Google Scholar 

  94. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

  99. 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.

    Article  CAS  PubMed  Google Scholar 

  100. 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).

    Article  CAS  PubMed  Google Scholar 

  101. 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).

    Article  CAS  PubMed  Google Scholar 

  102. Peters, J. M. et al. Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor α-deficient mice. J. Biol. Chem. 272, 27307–27312 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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).

    Article  CAS  PubMed  Google Scholar 

  107. 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).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

  109. Colin, S. et al. Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production. Eur. Heart J. 34, 2566–2574 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Umeda, Y. et al. Inhibitory action of gemfibrozil on cholesterol absorption in rat intestine. J. Lipid Res. 42, 1214–1219 (2001).

    CAS  PubMed  Google Scholar 

  111. Leibowitz, M. D. et al. Activation of PPARδ alters lipid metabolism in db/db mice. FEBS Lett. 473, 333–336 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. 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).

    Article  CAS  PubMed  Google Scholar 

  115. 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).

    Article  CAS  PubMed  Google Scholar 

  116. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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).

    Article  CAS  PubMed  Google Scholar 

  118. 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.

    Article  CAS  PubMed  Google Scholar 

  119. 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).

    Article  CAS  PubMed  Google Scholar 

  120. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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).

    Article  CAS  PubMed  Google Scholar 

  122. 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).

    CAS  PubMed  Google Scholar 

  123. Chehaibi, K. et al. PPAR-β/δ activation promotes phospholipid transfer protein expression. Biochem. Pharmacol. 94, 101–108 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. 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.

    Article  CAS  PubMed  Google Scholar 

  125. Voight, B. F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Altshuler, D. et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat. Genet. 26, 76–80 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. 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).

    Article  CAS  PubMed  Google Scholar 

  128. Ye, R. & Scherer, P. E. Adiponectin, driver or passenger on the road to insulin sensitivity? Mol. Metab. 2, 133–141 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Divakaruni, A. S. et al. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Proc. Natl Acad. Sci. USA 110, 5422–5427 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kusminski, C. M., Park, J. & Scherer, P. E. MitoNEET-mediated effects on browning of white adipose tissue. Nat. Commun. 5, 3962 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 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).

    Article  CAS  PubMed  Google Scholar 

  135. 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).

    Article  CAS  PubMed  Google Scholar 

  136. 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).

    Article  CAS  PubMed  Google Scholar 

  137. 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).

    Article  CAS  PubMed  Google Scholar 

  138. 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).

    Article  PubMed  Google Scholar 

  139. Lee, C.-H. et al. PPARδ regulates glucose metabolism and insulin sensitivity. Proc. Natl Acad. Sci. USA 103, 3444–3449 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Gan, Z. et al. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism. J. Clin. Invest. 123, 2564–2575 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 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).

    PubMed  PubMed Central  Google Scholar 

  142. 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).

    Article  CAS  PubMed  Google Scholar 

  143. Liu, S. et al. Role of peroxisome proliferator-activated receptor δ/β in hepatic metabolic regulation. J. Biol. Chem. 286, 1237–1247 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 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).

    Article  CAS  PubMed  Google Scholar 

  146. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 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).

    Article  CAS  PubMed  Google Scholar 

  148. 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).

    Article  CAS  PubMed  Google Scholar 

  149. Daoudi, M. et al. PPARβ/δ activation induces enteroendocrine L cell GLP-1 production. Gastroenterology 140, 1564–1574 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. 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).

    Article  CAS  PubMed  Google Scholar 

  151. Barroso, E. et al. PPARβ/δ ameliorates fructose-induced insulin resistance in adipocytes by preventing Nrf2 activation. Biochim. Biophys. Acta 1852, 1049–1058 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. Odegaard, J. I. et al. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 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).

    Article  CAS  PubMed  Google Scholar 

  154. 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).

    Article  CAS  PubMed  Google Scholar 

  155. Haas, J. T., Francque, S. & Staels, B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu. Rev. Physiol. 78, 181–205 (2016).

    Article  CAS  PubMed  Google Scholar 

  156. 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).

    Article  CAS  PubMed  Google Scholar 

  157. 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.

    Article  CAS  PubMed  Google Scholar 

  158. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Eckel-Mahan, K. L. et al. Reprogramming of the circadian clock by nutritional challenge. Cell 155, 1464–1478 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. 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).

    Article  CAS  PubMed  Google Scholar 

  161. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Matsusue, K. et al. Hepatic steatosis in leptin-deficient mice is promoted by the PPARγ target gene Fsp27. Cell Metab. 7, 302–311 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Hasenfuss, S. C. et al. Regulation of steatohepatitis and PPARγ signaling by distinct AP-1 dimers. Cell. Metab. 19, 84–95 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 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).

    Article  CAS  PubMed  Google Scholar 

  166. Yamauchi, T. et al. Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes. J. Clin. Invest. 108, 1001–1013 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 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).

    Article  CAS  PubMed  Google Scholar 

  168. 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).

    Article  CAS  PubMed  Google Scholar 

  169. 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).

    Article  CAS  PubMed  Google Scholar 

  170. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 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).

    Article  CAS  PubMed  Google Scholar 

  172. 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).

    Article  CAS  PubMed  Google Scholar 

  173. 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).

    Article  CAS  PubMed  Google Scholar 

  174. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 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).

    Article  CAS  PubMed  Google Scholar 

  176. 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).

    Article  CAS  PubMed  Google Scholar 

  177. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 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).

    Article  CAS  PubMed  Google Scholar 

  179. 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.

  180. Abdelmegeed, M. A. et al. PPARα expression protects male mice from high fat-induced nonalcoholic fatty liver. J. Nutr. 141, 603–610 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. 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.

    Article  CAS  PubMed  Google Scholar 

  182. Montagner, A. et al. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65, 1202–1214 (2016).

    Article  CAS  PubMed  Google Scholar 

  183. 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).

    Article  CAS  PubMed  Google Scholar 

  184. Ip, E. et al. Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology 38, 123–132 (2003).

    Article  CAS  PubMed  Google Scholar 

  185. 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).

    Article  CAS  PubMed  Google Scholar 

  186. Toyama, T. et al. PPARα ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats. Biochem. Biophys. Res. Commun. 324, 697–704 (2004).

    Article  CAS  PubMed  Google Scholar 

  187. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. 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).

    Article  CAS  PubMed  Google Scholar 

  190. Laurin, J. et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 23, 1464–1467 (1996).

    Article  CAS  PubMed  Google Scholar 

  191. Basaranoglu, M., Acbay, O. & Sonsuz, A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J. Hepatol. 31, 384 (1999).

    Article  CAS  PubMed  Google Scholar 

  192. 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).

    Article  CAS  PubMed  Google Scholar 

  193. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  194. 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).

    Article  CAS  PubMed  Google Scholar 

  195. 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).

    Article  CAS  PubMed  Google Scholar 

  196. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. 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).

    CAS  PubMed  Google Scholar 

  199. Hellemans, K. et al. Peroxisome proliferator-activated receptor-β signaling contributes to enhanced proliferation of hepatic stellate cells. Gastroenterology 124, 184–201 (2003).

    Article  CAS  PubMed  Google Scholar 

  200. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Semple, R. K., Chatterjee, V. K. K. & O'Rahilly, S. PPARγ and human metabolic disease. J. Clin. Invest. 116, 581–589 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. 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.

    Article  CAS  PubMed  Google Scholar 

  203. Kernan, W. N. et al. Pioglitazone after ischemic stroke or transient ischemic attack. N. Engl. J. Med. 374, 1321–1331 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. 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).

    Article  CAS  PubMed  Google Scholar 

  205. Levin, D. et al. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia 58, 493–504 (2015).

    Article  CAS  PubMed  Google Scholar 

  206. Tuccori, M. et al. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ 352, i1541 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Whitehead, J. P. Diabetes: new conductors for the peroxisome proliferator-activated receptor γ (PPARγ) orchestra. Int. J. Biochem. Cell Biol. 43, 1071–1074 (2011).

    Article  CAS  PubMed  Google Scholar 

  208. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. 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).

    Article  CAS  PubMed  Google Scholar 

  210. 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).

    Article  CAS  PubMed  Google Scholar 

  211. Joshi, S. R. Saroglitazar for the treatment of dyslipidemia in diabetic patients. Expert Opin. Pharmacother. 16, 597–606 (2015).

    Article  CAS  PubMed  Google Scholar 

  212. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  213. 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).

    Article  CAS  PubMed  Google Scholar 

  214. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. 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).

    Article  CAS  PubMed  Google Scholar 

  216. 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).

    Article  CAS  PubMed  Google Scholar 

  217. 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).

    Article  CAS  PubMed  Google Scholar 

  218. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. 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).

    Article  CAS  PubMed  Google Scholar 

  220. Cymabay Therapeutics. Corporate presentation. http://content.equisolve.net/cymabay/media/9af11b3859e3b4fa04eff0f43424ffb5.pdf (2016).

  221. He, B. K. et al. In vitro and in vivo characterizations of chiglitazar, a newly identified PPAR pan-agonist. PPAR Res. 2012, 546548 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02121717 (2016).

  223. Tee, J. Phase Ib clinical trial demonstrates positive finding for a new treatment for Type 2 diabetes. Diabetes Manage. 2, 16 (2012).

    Google Scholar 

  224. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01042106 (2013).

  225. 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).

    Article  CAS  PubMed  Google Scholar 

  226. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

Authors

Contributions

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

Corresponding author

Correspondence to Bart Staels.

Ethics declarations

Competing interests

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

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2016.135

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing