Peroxisome Proliferator-Activated Receptor-γ Calls for Activation in Moderation: Lessons from Genetics and Pharmacology
- 1 December 2004
- journal article
- review article
- Published by The Endocrine Society in Endocrine Reviews
- Vol. 25 (6), 899-918
- https://doi.org/10.1210/er.2003-0036
Abstract
The peroxisome proliferator-activated receptor gamma (PPARgamma) is a prototypical member of the nuclear receptor superfamily and integrates the control of energy, lipid, and glucose homeostasis. PPARgamma can bind a variety of small lipophilic compounds derived from metabolism and nutrition. These ligands, in turn, determine cofactor recruitment to PPARgamma, regulating the transcription of genes in a variety of metabolic pathways. PPARgamma 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 consequences of PPARgamma 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 PPARgamma partial agonists and antagonists, as well as pan-PPAR agonists. The results of these studies have added to the understanding of PPARgamma function, allowing us to hypothesize a general mechanism of PPARgamma action and speculate on future trends in the use of PPARgamma as a target in the treatment of type II diabetes.Keywords
This publication has 98 references indexed in Scilit:
- The effects of the Pro12Ala polymorphism of thePPARγ-2gene on lipid metabolism interact with body size at birthClinical Genetics, 2003
- Identification of a Novel Peroxisome Proliferator-Activated Receptor (PPAR) γ Promoter in Man and Transactivation by the Nuclear Receptor RORα1Biochemical and Biophysical Research Communications, 2001
- Activation of PPARδ alters lipid metabolism in db/db miceFEBS Letters, 2000
- Inhibitory Effect of a Proline-to-Alanine Substitution at Codon 12 of Peroxisome Proliferator-Activated Receptor-γ 2 on Thiazolidinedione-Induced AdipogenesisBiochemical and Biophysical Research Communications, 2000
- Thiazolidinediones Suppress Endothelin-1 Secretion from Bovine Vascular Endothelial Cells: A New Possible Role of PPARγ on Vascular Endothelial FunctionBiochemical and Biophysical Research Communications, 1999
- PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoterFEBS Letters, 1998
- Obesity Associated with a Mutation in a Genetic Regulator of Adipocyte DifferentiationNew England Journal of Medicine, 1998
- Molecular Scanning of the Human Peroxisome Proliferator Activated Receptor γ (hPPARγ) Gene in Diabetic Caucasians: Identification of a Pro12Ala PPARγ2 Missense MutationBiochemical and Biophysical Research Communications, 1997
- A transcriptional co-repressor that interacts with nuclear hormone receptorsNature, 1995
- Identification of Two mPPAR Related Receptors and Evidence for the Existence of Five Subfamily MembersBiochemical and Biophysical Research Communications, 1993