There is a growing interest in peroxisome proliferator activated receptors (PPARs) as major players in the regulation of lipid and carbohydrate metabolism. Drugs targeting PPARs were in fact shown of major relevance for the treatment of diseases associated with aging such as arteriosclerosis and diabetes. However, a variety of toxic effects associated with PPAR ligands administration has been documented, including hepatocarcinogenesis, that may severely limit their therapeutic use. A better comprehension of the multiplicity of PPAR physiological functions is therefore mandatory for the development of novel safer drugs. We here describe the generation of a novel transgenic mouse for the detection of the generalized activities of PPARs, the PPRE-Luc reporter mouse. In this model luciferase expression is under control of a PPAR-inducible promoter in all target organs. By optical imaging and ex vivo analysis, we were able to demonstrate a remarkable gender specificity of the PPAR transcriptional activity in liver. In fact, in the liver of female PPRE-Luc, the PPAR reporter transgene is more than one order of magnitude less expressed, thus leading to conclude that the signaling in female is much less activated than in males. This low activation is not influenced by diet or hormonal manipulations as here demonstrated by treatments with high fat diet or gonad removal and hormone replacement. The extent of the gender difference in PPAR transcriptional activity and the ineffectiveness of hormone treatments or diet to significantly elevate liver PPAR activity in females, led us to hypothesize that gender-specific epigenetic events occurring during development may affect the PPAR signalling in the liver. The study sets the ground for the understanding of the differential susceptibility of the two genders to metabolic disorders; furthermore, the model generated provides a novel opportunity for the molecular characterization of PPAR activity in patho-physiological conditions.