Growth, adipose, brain and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor b(d

To determine the physiological roles of peroxisome proliferator-activated receptor b (PPARb), null mice were constructed by targeted disruption of the ligand binding domain of the murine PPARb gene. Homozygous PPARb-null term fetuses were smaller than controls, and this phenotype persisted postnatally. Gonadal adi-pose stores were smaller, and constitutive mRNA levels of CD36 were higher, in PPARb-null mice than in con-trols. In the brain, myelination of the corpus callosum was altered in PPARb-null mice. PPARb was not required for induction of mRNAs involved in epidermal differentiation induced by O-tetradecanoylphorbol-13-acetate (TPA). The hyperplastic response observed in the epidermis after TPA application was significantly greater in the PPARb-null mice than in controls. Inflammation induced by TPA in the skin was lower in wild-type mice fed sulindac than in similarly treated PPARb-null mice. These results are the first to provide in vivo evidence of significant roles for PPARb in development, myelination of the corpus callosum, lipid metabolism, and epidermal cell proliferation. In the past 10 years, specific roles for peroxisome prolifera-tor-activated receptor a (PPARa) and PPARg have emerged while information defining PPARb-dependent processes is lacking. PPARs are members of the nuclear receptor super