Molecular basis of selective PPARγ modulation for the treatment of Type 2 diabetes

doi:10.1016/j.bbalip.2007.03.004

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Volume 1771, Issue 8, August 2007, Pages 1094-1107

https://doi.org/10.1016/j.bbalip.2007.03.004 Get rights and content

Abstract

Peroxisome proliferator-activated receptors (PPARs) (α, β/δ and γ) are lipid sensors capable of adapting gene expression to integrate various lipid signals. As such, PPARs are also very important pharmaceutical targets, and specific synthetic ligands exist for the different isotypes and are either currently used or hold promises in the treatment of major metabolic disorders. In particular, compounds of the class of the thiazolinediones (TZDs) are PPARγ agonists and potent insulin-sensitizers. The specific but still broad expression patterns of PPARγ, as well as its implication in numerous pathways, constitutes also a disadvantage regarding drug administration, since this potentially increases the chance to generate side-effects through the activation of the receptor in tissues or cells not affected by the disease. Actually, numerous side effects associated with the administration of TZDs have been reported. Today, a new generation of PPARγ modulators is being actively developed to activate the receptor more specifically, in a cell and time-dependent manner, in order to induce a specific subset of target genes only and modulate a restricted number of metabolic pathways. We will discuss here why and how the development of such selective PPARγ modulators is possible, and summarize the results obtained with the published molecules.

Introduction

Peroxisome Proliferator-Activated Receptor (PPAR) α (NR1C1), β/δ (NR1C2) and γ (NR1C3) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily [1]. PPARs are lipid sensors capable of adapting gene expression to integrate various lipid signals coming from intracellular signaling pathways, from inter-organ crosstalk or even from the diet [2]. Given their partially overlapping yet specific expression patterns, the three receptors cooperate to efficiently regulate metabolic functions [3], [4] as well as other cellular processes such as proliferation, differentiation or apoptosis that are essential to the fate of the tissues and organs in which they are expressed [2], [5].

PPARs have a canonical nuclear receptor organization. The N-terminal A/B domain does not seem to be structured and harbors a weak ligand-independent transactivation function called AF-1. The C domain binds DNA via a two zinc-finger motif that is the hallmark of the nuclear receptor superfamily. Following the D domain which is a hinge region, the E domain harbors the ligand binding domain (LBD) and is endowed with a ligand-dependent transactivation function referred to as AF-2. This domains allows PPARs to function as lipid or xenobiotic sensors, since, as we will see later on, the binding pocket is large and can accommodate numerous structures. In addition, the E domain also offers the main surfaces for dimerization as well as for interaction with regulatory proteins called coregulators, a key aspect of PPAR modulation that we will also further develop in this review.

PPARs are very important pharmaceutical targets, as specific synthetic ligands exist for the different isotypes and are either currently used or hold promises in the treatment of major metabolic disorders [6]. More precisely, fibrates are PPARα agonists used as plasma lipid-lowering drugs in the treatment of hyperlipidaemia. Compounds of the class of the thiazolinediones (TZDs), such as Troglitazone, Pioglitazone and Rosiglitazone are PPARγ agonists and potent insulin-sensitizers, which have been tested and compared in a number of clinical trials for the treatment of type 2 diabetes (reviewed in [7]).

The PPARγ gene can be transcribed into three mRNA species, i.e. PPARγ1, PPARγ2, and PPARγ3 [8], [9]. Little is known about the expression pattern of PPARγ3, except that it appears to be the predominant PPARγ type in macrophages. PPARγ1 seems ubiquitously expressed, whereas PPARγ2 expression is confined to the adipose tissue, underscoring the importance of the PPARγ form for adipocyte physiology. Both the γ1 and γ2 isoforms display adipogenic potential although PPARγ2 seems slightly more potent owing to higher affinity with certain coactivators [10]. The specific genetic invalidation of PPARγ2 in the adipose tissue revealed that both isoforms are important for adipocyte physiology [11], [12]. However, it is so far not clear which specific role each isoform plays in glucose and lipid homeostasis. The specificity of action may in part rely on their different tissue expression patterns, but also in the modulation of receptor activity by the presence in PPARγ2 of an additional domain of 30 residues at the N-terminus.

Section snippets

The causes of type 2 diabetes

Type 2 diabetes is clinically defined by a hyperglycemia in fasted patients, resulting primarily from a desensitization to the hypoglycaemic actions of insulin. The etiology of type 2 diabetes is however a complex issue, since it is a heterogeneous disease with multiple and intricate causes [13], which may be of relative importance depending upon the genetic background and life-style of the subjects affected [14]. Nevertheless, obesity and dyslipidaemia constitute two overwhelming factors in

PPARγ partial activation versus modulation

These observed or potential side-effects are of great concern and raise the question of whether the modulation of PPAR activation may become safer while retaining its efficacy. Pharmaceutical developments have until recently focused on more potent and specific activators of PPARγ, the rational being to decrease the doses used during the treatment, thereby reducing the non-specific interactions of these drugs with other cellular components. However, this strategy was greatly challenged when

PPARs can bind a wide variety of ligands owing to their large ligand binding pocket

SPPARγMs are ligands whose binding induces a specific conformation change of the receptor, translating into the induction of a specific subset of target genes. A particularity of the PPAR sub-family is that the diversity of functions in which they are implicated is also reflected by the diversity of ligands that can be accommodated within their ligand binding pocket. Indeed, PPARs are activated by a wide range of naturally occurring or metabolized lipids derived from the diet or from

What is the profile of a good SPPARγM?

The SPPARγM described so far in the literature have been often only partly characterized, regarding ligand binding mode, conformational changes, coregulator recruitment, target gene activation and physiological response. To allow a better overview and the comparison of the different SPPARγMs, we summarized in a table the most important properties of each of these molecules (Table 1). It is hence very difficult to link with certitude a specific conformation change or the recruitment of a

Acknowledgements

This work was supported by grants from the National Research Project 50, the Swiss National Science Foundation, and the Etat de Vaud.

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¹: The authors contributed equally to this work.

²: Current address: IGBMC, Room 3013, 1 Rue Laurent Fries, BP 10142, 67404 Illkirch, France.

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ReviewMolecular basis of selective PPARγ modulation for the treatment of Type 2 diabetes

Abstract

Introduction

Section snippets

The causes of type 2 diabetes

PPARγ partial activation versus modulation

PPARs can bind a wide variety of ligands owing to their large ligand binding pocket

What is the profile of a good SPPARγM?

Acknowledgements

Prog. Lipid Res.

Nat. Med.

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

Lancet

Cell

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

J. Pharmacol. Sci.

Eur. J. Pharmacol.

Clin. Ther.

Endocr. Pract.

J. Biol. Chem.

Trends Biochem. Sci.

Curr. Opin. Cell Biol.

J. Steroid Biochem. Mol. Biol.

Mol. Cell

J. Biol. Chem.

J. Mol. Biol.

Structure

Mol. Cell

Cell

Cell

J. Biol. Chem.

Cell

Cell

Cell

Curr. Opin. Cell Biol.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

A unified nomenclature system for the nuclear receptor superfamily

Cell

Transcriptional regulation of metabolism

Physiol. Rev.

Involvement of PPAR nuclear receptors in tissue injury and wound repair

J. Clin. Invest.

Therapeutic roles of peroxisome proliferator-activated receptor agonists

Diabetes

Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients

Diabetes

Selective disruption of PPARgamma 2 impairs the development of adipose tissue and insulin sensitivity

Proc. Natl. Acad. Sci. U. S. A.

The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-gamma2 isoform

Diabetes

Obesity, peroxisome proliferator-activated receptor, and atherosclerosis in Type 2 diabetes

Arterioscler. Thromb. Vasc. Biol.

Genetic factors in type 2 diabetes: the end of the beginning?

Science

Adipokines: inflammation and the pleiotropic role of white adipose tissue

Br. J. Nutr.

How obesity causes diabetes: not a tall tale

Science

Review
Molecular basis of selective PPARγ modulation for the treatment of Type 2 diabetes