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Review
. 2017 Apr 3;127(4):1202-1214.
doi: 10.1172/JCI88894. Epub 2017 Apr 3.

Distinct but complementary contributions of PPAR isotypes to energy homeostasis

Vanessa Dubois, Jérôme Eeckhoute, Philippe Lefebvre, Bart Staels
Review

Distinct but complementary contributions of PPAR isotypes to energy homeostasis

Vanessa Dubois et al. J Clin Invest. .

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.

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Conflict of interest statement

Conflict of interest: B. Staels is an advisor for Genfit SA.

Figures

Figure 1
Figure 1. PPARα activation stimulates FA and triglyceride metabolism.
During fasting (yellow), FAs released from WAT are taken up by the liver and transported to mitochondria, where FAO takes place, to produce acetyl-CoA (AcCoA), which can be further converted to ketone bodies and serve as fuel for peripheral tissues. In the fed state (green), acetyl-CoA is shuttled to the cytosol, where DNL takes place. The effects of PPARα activation and PPARα _target genes are indicated in pink. FAO is also stimulated by PPARα in WAT and SKM. By regulating hepatic apolipoprotein synthesis, PPARα activation decreases plasma levels of triglycerides (TG) and LDL-C and increases HDL-C. PPARα also acts on BAT, gut, and pancreas, but its central effects are unclear. Blue brackets indicate PPARα actions that are mainly restricted to mice and do not occur (e.g., peroxisome proliferation, reduced liver fat content) or occur to a lesser extent (e.g., reduced APO-B production) in humans. ACAD, acyl-CoA dehydrogenase; ACC, acetyl-CoA carboxylase; CM, chylomicron; CPT, carnitine palmitoyltransferase; FACoA, fatty acyl-CoA; FAS, fatty acid synthase; FATP, fatty acid transport protein.
Figure 2
Figure 2. PPARγ activation increases whole-body insulin sensitivity.
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.
Figure 3
Figure 3. PPARβ/δ activation enhances glucose and lipid homeostasis.
In SKM, PPARβ/δ activation (effects are indicated in pink) favors fiber type switching toward type I oxidative fibers, which have a higher glucose-handling capacity compared with type II fibers. PPARβ/δ also augments FAO in SKM, liver, and WAT and enhances hepatic glucose metabolism and pancreatic β cell function. PPARβ/δ activation decreases FAs, triglycerides, and LDL-C and increases HDL-C levels in blood. Metabolic effects of PPARβ/δ agonism also take place in brain and gut.
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