Nuclear hormone receptors are a model for ligand activated transcription. A subfamily of three nuclear receptors, the peroxisome proliferators-activated receptors, binds fatty acids to regulate a variety of biological processes. One of these, PPAR delta, has a broad and even tissue distribution providing few clues as to its function. Recently, a high affinity synthetic ligand to this receptor has greatly facilitated the study of gene regulation by this receptor. One of the hallmarks of PPAR delta activation is an increase in serum high-density lipoprotein cholesterol levels. Because low HDLc is a hallmark of the metabolic syndrome and a significant risk factor for cardiovascular disease we attempted to discover the mechanism by which ligand activation of PPAR delta raises HDLc in mice. Surprisingly we found that PPAR delta is able to regulate the main protein component of HDL, apolipoprotein AI, in adipose tissue. Amazingly, adipose tissue transplantation of AZIP/F1 or PPAR delta knockout animals was able to rescue the effect of ligand. Recent studies have highlighted the role of PPAR alpha in oxidative metabolism. To study the effect of PPAR alpha activation in a state of increased oxidative metabolism we utilized a regimen of caloric restriction. Paradoxically PPAR alpha and PPAR alpha ligand administration during caloric restriction decreased weight loss. Analysis of gene expression revealed that activation of the fatty acid synthesis pathway in liver could be responsible for this phenotype

Macrophage activation by the proinflammatory cytokine interferon-gamma (IFN-gamma) is a critical component of the host innate response to bacterial pathogenesis. However, the precise nature of the IFN-gamma-induced activation pathway is not known. Here we show using genome-wide expression and chromatin-binding profiling that IFN-gamma induces the expression of many nuclear genes encoding mitochondrial respiratory chain machinery via activation of the nuclear receptor ERR alpha (estrogen-related receptor alpha, NR3B1). Studies with macrophages lacking ERR alpha demonstrate that it is required for induction of mitochondrial reactive oxygen species (ROS) production and efficient clearance of Listeria monocytogenes (LM) in response to IFN-gamma. As a result, mice lacking ERR alpha are susceptible to LM infection, a phenotype that is localized to bone marrow-derived cells. Furthermore, we found that IFN-gamma-induced activation of ERR alpha depends on coactivator PGC-1 beta (peroxisome proliferator-activated receptor gamma coactivator-1 beta), which appears to be a direct target for the IFN-gamma/STAT-1 signaling cascade. Thus, ERR alpha and PGC-1 beta act together as a key effector of IFN-gamma-induced mitochondrial ROS production and host defense.