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PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD

Key Points

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

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

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

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

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

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

Abstract

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

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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).

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Acknowledgements

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

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

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Correspondence to Bart Staels.

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

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

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