PPAR gamma agonist and antagonist

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPAR gamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPAR gamma activity observed in heterozygous PPAR gamma-deficient mice or the Pro 12 Ala polymorphism in human PPAR gamma has been shown to prevent insulin resistance and obesity induced by a high-fat (HF) diet. We investigated whether functional antagonism toward PPAR gamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that moderate reduction of PPAR gamma with an RXR antagonist or a PPAR gamma antagonist decreases triglyceride (TG) content in white adipose tissue, skeletal muscle and liver. These inhibitors potentiate leptin's effects and stimulated adiponectin levels, which increases fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, severe reduction of PPAR gamma by treatment of heterozygous PPAR gamma-deficient mice with an RXR antagonist or a PPAR gamma antagonist depletes white adipose tissue and markedly decreases leptin and adiponectin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggest that appropriate functional antagonism of PPAR gamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.