Energy in the Balance

The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs) are ligand-activated transcription factors that coordinately regulate gene expression. This PPAR-RXR transcriptional complex plays a critical role in energy balance, including triglyceride metabolism, fatty acid handling and storage, and glucose homeostasis: processes whose dysregulation characterize obesity, diabetes, and atherosclerosis. PPARs and RXRs are also involved directly in inflammatory and vascular responses in endothelial and vascular smooth muscle cells. New insights into fundamental aspects of PPAR and RXR biology, and their actions in the vasculature, continue to appear. Although RXRs are obligate heterodimeric partners for PPAR action, the part that RXRs, and their endogenous retinoid mediators, exert in the vessel wall is less well understood. Biological insights into PPAR-RXRs may help inform interpretation of clinical trials with synthetic PPAR agonists and prospects for future PPAR therapeutics. Importantly, the extensive data establishing a key role for PPARs and RXRs in energy balance, inflammation, and vascular biology stands separately from the clinical experience with any given synthetic PPAR agonist. Both the basic science data and the clinical experience with PPAR agonists identify the need to better understand these important transcriptional regulators. (Circ Res. 2011;108:1002-1016.)