PPARadigms and PPARadoxes: expanding roles for PPAR g in the control of lipid metabolism

The nuclear receptor PPAR g is a central regulator of adipose tissue development and an important modulator of gene expression in a number of specialized cell types including adipocytes, epithelial cells, and macrophages. PPAR g signaling pathways impact both cellular and systemic lipid metabolism and have links to obesity, diabetes, and cardiovascular disease. The ability to activate this receptor with small molecule ligands has made PPAR g an attractive target for intervention in human metabolic disease. As our understanding of PPAR g biology has expanded, so has the therapeutic potential of PPAR g ligands. Recent studies have provided insight into the paradoxical relationship between PPAR g and metabolic disease and established new paradigms for the control of lipid metabolism. This review focuses on recent advances in PPAR g biology in the areas of adipocyte differentiation, insulin resistance, and atherosclerosis. —Walczak, R., and P. Tontonoz. PPARadigms and PPARadoxes: expanding roles for PPAR g in the control of lipid metabolism. J. Lipid. Res. 2002. 43: 177–186. Supplementary key words peroxisome proliferator-activated receptors • adipocyte • adipose tissue • diabetes • obesity The past 10 years have seen a new paradigm emerge for the transcriptional regulation of metabolic pathways with the discovery of the peroxisome proliferator-activated receptors (PPAR a , PPAR g , and PPAR d ), a trio of nuclear receptors activated by lipids. Characterization of PPARs led to the realization that certain nuclear receptors have evolved to recognize specific metabolic intermediates in the pathways that they control. Unlike the steroid receptors, which bind a single high affinity ligand, PPARs have the ability to recognize a range of structurally diverse molecules. The importance of this property became clear when it was discovered that the physiologic activators of these receptors are likely to be native and modified polyunsaturated fatty acids. Thus, the PPARs are transcription factors that regulate expression of genes involved in lipid metabolism, and the physiologic ligands for these receptors are