Distinct but complementary contributions of PPAR isotypes to energy homeostasis
Vanessa Dubois, Jérôme Eeckhoute, Philippe Lefebvre, Bart Staels
Vanessa Dubois, Jérôme Eeckhoute, Philippe Lefebvre, Bart Staels
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Review Series

Distinct but complementary contributions of PPAR isotypes to energy homeostasis

Abstract

Peroxisome proliferator–activated receptors (PPARs) regulate energy metabolism and hence are therapeutic targets in metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. While they share anti-inflammatory activities, the PPAR isotypes distinguish themselves by differential actions on lipid and glucose homeostasis. In this Review we discuss the complementary and distinct metabolic effects of the PPAR isotypes together with the underlying cellular and molecular mechanisms, as well as the synthetic PPAR ligands that are used in the clinic or under development. We highlight the potential of new PPAR ligands with improved efficacy and safety profiles in the treatment of complex metabolic disorders.

Authors

Vanessa Dubois, Jérôme Eeckhoute, Philippe Lefebvre, Bart Staels

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Figure 2

PPARγ activation increases whole-body insulin sensitivity.

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PPARγ activation increases whole-body insulin sensitivity. In WAT, PPARγ...
In WAT, PPARγ activation (effects are indicated in pink) enhances FA uptake and storage, lipogenesis, and adipogenesis (lipid steal action). PPARγ activation lowers circulating FA levels, alleviating lipotoxicity and increasing insulin sensitivity. PPARγ agonism induces adiponectin production by WAT, further enhancing insulin sensitivity and lowering blood glucose. PPARγ also exerts metabolic effects on BAT, brain, and pancreas. Increased hepatic steatosis upon PPARγ activation occurs in mice but not in humans (blue brackets), who display increased hepatic insulin sensitivity due to reduced FA flux from WAT.