PPAR g Is Required for Placental , Cardiac , and Adipose Tissue Development

They thus provide a plausible link between the induction of physiological PPAR␥ targets and systemic insulin sensitization (Spiegelman and Flier, 1996). Summary PPARs belong to a subclass of nuclear hormone receptors that, like the retinoic acid, vitamin D, and thyroid The nuclear hormone receptor PPAR␥ promotes adi-pogenesis and macrophage differentiation and is a hormone receptors, execute their transcriptional functions as heterodimers with the retinoid X receptor (RXR) primary pharmacological target in the treatment of type II diabetes. Here, we show that PPAR␥ gene (Kliewer et al., 1992a, 1992b). Ample experimental evidence suggests that PPAR–RXR heterodimers serve as knockout results in two independent lethal phases. Initially, PPAR␥ deficiency interferes with terminal dif-the core signaling units. These include the demonstration of high-affinity heterodimerization necessary for ferentiation of the trophoblast and placental vascular-ization, leading to severe myocardial thinning and DNA binding in vitro (Kliewer et al., 1992b); the efficacy of RXR-specific ligands in promoting typical PPAR␥ death by E10.0. Supplementing PPAR␥ null embryos with wild-type placentas via aggregation with tetra-activities in cultured cells, such as adipogenesis and macrophage differentiation, alone and in synergy with ploid embryos corrects the cardiac defect, implicating a previously unrecognized dependence of the devel-and the ability of RXR-specific ligands to oping heart on a functional placenta. A tetraploid-rescued mutant surviving to term exhibited another lethal relieve symptoms of insulin-resistance and type II diabetes in animals (Mukherjee et al., 1997). combination of pathologies, including lipodystrophy and multiple hemorrhages. These findings both con-The involvement of PPAR␥ in key metabolic processes pertaining to lipid homeostasis in clinically important firm and expand the current known spectrum of physiological functions regulated by PPAR␥. situations such as obesity, type II diabetes, and athero-sclerosis prompted us to establish a knockout animal model to critically assess its functions. We report here Introduction the generation of PPAR␥-deficient mice and the discovery of unanticipated essential roles of the receptor The nuclear hormone receptors comprise an extended during pre-and postnatal development. First, PPAR␥ family of transcription factors that utilize ligand-borne is required for epithelial differentiation of trophoblast signals to regulate genes governing various aspects of tissue, which proves critical for proper placental vas-eukaryote homeostasis, development, and reproduction cularization. These defects lead to myocardial thinning, (Kastner et al., 1995; Mangelsdorf et al., 1995). Peroxi-which can be fully circumvented through selective res-some proliferator–activated receptors (PPARs) ␣, ␥, and cue of the placental pathology, thus revealing a novel ␦ constitute a subfamily of …