Peroxisome Proliferator-Activated Receptor-γ Calls for Activation in Moderation: Lessons from Genetics and Pharmacology

0163-769X/04/$20.00/0 Printed in U.S.A. Endocrine Reviews 25(6):899 –918 Copyright © 2004 by The Endocrine Society doi: 10.1210/er.2003-0036 Peroxisome Proliferator-Activated Receptor-␥ Calls for Activation in Moderation: Lessons from Genetics and Pharmacology CHRIS KNOUFF AND JOHAN AUWERX Institut de Génétique et de Biologie Moléculaire et Cellulaire (C.K., J.A.), Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, and Institut Clinique de la Souris (J.A.), Génopole Strasbourg, 67404 Illkirch, France The peroxisome proliferator-activated receptor ␥ (PPAR␥) is a prototypical member of the nuclear receptor superfamily and integrates the control of energy, lipid, and glucose homeostasis. PPAR␥ can bind a variety of small lipophilic compounds derived from metabolism and nutrition. These ligands, in turn, determine cofactor recruitment to PPAR␥, regulating the transcription of genes in a variety of metabolic pathways. PPAR␥ is the main target of the thiazolidinedione class of insulin-sensitizing drugs, which are currently a mainstay of therapy for type 2 diabetes. However, this therapy has a number of side effects. Here, we review the clinical conse- quences of PPAR␥ polymorphisms in humans, as well as several studies in mice using general or tissue-specific knockout techniques. We also discuss the recent pharmacological literature describing a variety of new PPAR␥ partial agonists and antagonists, as well as pan-PPAR agonists. The results of these studies have added to the understanding of PPAR␥ function, allowing us to hypothesize a general mechanism of PPAR␥ action and speculate on future trends in the use of PPAR␥ as a target in the treatment of type II diabetes. (Endocrine Reviews 25: 899 –918, 2004) I. Introduction: The Biology of Peroxisome Proliferator-Activated Receptor-␥ (PPAR␥) in a Nutshell II. What Mutations in the Human PPAR␥ Gene Teach Us A. Hypomorphic and loss-of-function alleles: Pro12Ala B. Dominant-negative PPAR␥ alleles C. Gain-of-function PPAR␥ mutations: Pro113Gln D. Other mutations E. Summary III. Releasing the Power of Mouse Genetics on PPAR␥ (Table 1) A. Germline mutations of PPAR␥ B. Tissue-specific mutations of PPAR␥ IV. The Pharmacology of PPAR␥: Drugs to Mimic Mutations (Table 2) A. Full agonists B. Partial agonists C. Antagonists D. PPAR coagonists E. Summary V. Overview and Perspectives I. Introduction: The Biology of Peroxisome Proliferator-Activated Receptor-␥ (PPAR␥) in a Nutshell T HE ABILITY TO maintain metabolic homeostasis in the face of differing nutritional and environmental states is essential for survival. One way this is accomplished is through the transcriptional control by nuclear receptors of genes that regulate a wide variety of metabolic pathways. The PPAR␥ is a prototypical member of the nuclear receptor superfamily and integrates the control of energy, lipid, and glucose homeostasis (1–9). Like all nuclear receptors, PPAR␥ has a modular structure that comprises: the N-terminal A/B domain, harboring a ligand-independent transcriptional activation function (AF-1); the DNA-binding domain, which contains two zinc fingers; and the C-terminal region, which contains the ligand-binding domain and the ligand-dependent activation domain AF-2 (reviewed in Refs. 10 –13). PPAR␥ forms a heterodimer with retinoic X receptor-␣ (RXR␣) and binds to PPAR response elements (PPREs) in the regulatory regions of target genes. In a basal state, the PPAR␥/RXR␣ heterodimer is bound to corepressor proteins such as retinoblastoma (RB) (14, 15), nuclear receptor corepressor (16, 17), and silencing mediator of retinoid and thyroid receptors (17, 18). The activity of PPAR␥ is governed by the binding of small lipophilic ligands. Endogenous ligands include polyunsaturated fatty acids and eicosanoids derived from nutrition or metabolic pathways, some of which may be regulated by PPAR␥ (19 –21). Synthetic ligands, including thiazolidinediones (TZDs) (22), tyrosine-based agonists (23), and nonsteroidal antiinflammatory drugs (NSAIDs) (24), include the most potent activators of PPAR␥ and are discussed Abbreviations: ABC, ATP-binding cassette; AF-1, activation function 1; AGA, appropriate for gestational age; BMI, body mass index; DZ, dizygotic; FFA, free fatty acids; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LXR, liver X receptor; MZ, monozygotic; NSAID, nonsteroidal antiinflammatory drug; oxLDL, oxidized LDL; PPAR␥, peroxisome proliferator-activated receptor-␥; PPRE, PPAR response element; RB, retinoblastoma; RXR␣, retinoic X receptor-␣; SGA, small for gestational age; SNP, single nucleotide polymorphism; SRC, steroid receptor coactivator; TIF-2, transcriptional intermediary factor 2; TZD, thiazolidinedione; WAT, white adipose tissue. Endocrine Reviews is published bimonthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community. 899 900 Endocrine Reviews, December 2004, 25(6):899 –918 below (reviewed in Refs. 8 and 25). Binding of these ligands in the ligand-binding pocket alters the conformation of PPAR␥, which results in the release of corepressors and recruitment of coactivators, such as those of the p160 steroid receptor cofactor family (13, 26 –29) and p300/cAMP response element binding protein (CREB)-binding protein (30 – 32), resulting in increased transcriptional activation of target genes. Specificity of target genes is determined not only by the nature of the response element in the promoter, but also by which coactivator is recruited to the PPAR␥/RXR␣ heterodimer, which in turn is affected by the type of ligand bound. A Westernized life style, characterized by high caloric intake and a lack of physical exercise, exposes people to chronically higher levels of free fatty acids (FFA), the endogenous ligands for PPAR␥, which cause the feed-forward activation of genetic programs leading to a metabolic state favorable for the development of obesity. The actions of PPAR␥ are mediated by two protein isoforms, the widely expressed PPAR␥1 and adipose tissuerestricted PPAR␥2 (33, 34). Expression of each isoform is driven by a specific promoter that confers the distinct tissue expression patterns. These isoforms are produced from a single gene by alternative splicing and differ only by an additional 30 amino acids (28 in mice) in the N terminus of PPAR␥2 (35–37). The two additional amino acids in human PPAR␥2 are due to translation initiation in human PPAR␥1 at a methionine codon two residues downstream from the start codon used in mouse PPAR␥1. This addition of 30 N-terminal amino acids results in a 5- to 6-fold increase in the activation function of the N-terminal ligand-independent activation domain (AF-1) (38). There are also two other mRNA variants of PPAR␥, which differ in the 5⬘-untranslated region but give rise to proteins identical to PPAR␥1: PPAR␥3, which is restrict (...truncated)