Differential Expression of Peroxisome Proliferator-Activated Receptor-α, -β, and -γ during Rat Embryonic Development.

The expression patterns of the three different peroxisome proliferator-activated receptor (PPAR) isotypes have been determined during rat embryonic development by in situ hybridization. The expression of PPARa starts late in development, with increasing levels in organs such as liver, kidney, intestine, and pancreas, in which it will also be present later in adulthood to regulate its specific target genes. PPARa is also transiently expressed in the embryonic epidermis and central nervous system. PPARg presents a very restricted pattern of expression, being strongly expressed in brown adipose tissue, in which differentiation it has been shown to participate. Like PPARa, it is also expressed transiently in the central nervous system. Interestingly, PPARa, -b and -g are coexpressed at high levels in brown adipose tissue. Finally, the high and ubiquitous expression of PPARb suggests some fundamental role(s) that this receptor might play throughout development. (Endocrinology 139: 2748–2754, 1998) P proliferator-activated receptors (PPARs) are lipid-activatable transcription factors that belong to the nuclear hormone receptor superfamily (see Ref. 1 for a review). To date, three isotypes of PPARs have been described in amphibians, rodents, and humans: PPARa, PPARb (also called d, NUC-1, or FAAR), and PPARg (2–10). PPARs were shown to be activated by substances that induce peroxisome proliferation (2, 3) as well as by natural fatty acids (4, 11). It is only recently that fatty acids, some eicosanoids, and some hypolipidemic and antidiabetic drugs have been shown to directly bind to PPARs (12–18; see Ref. 19 for a review). PPAR target genes encode enzymes involved in peroxisomal and mitochondrial b-oxidation, ketone body synthesis, and microsomal v-hydroxylation, as well as the production of fatty acid binding proteins, apolipoproteins, lipoprotein lipase, malic enzyme, phosphoenolpyruvate carboxykinase, and the brown adipose tissue (BAT) uncoupling protein (see Refs. 1, 20, and 21 for reviews; 22). Thus, PPARs play key roles in different aspects of lipid metabolism and homeostasis. Consistent with the different pathways they regulate, PPARs were shown to be expressed in a wide range of tissues of the adult organism (3, 7, 23–25). We have shown recently, using in situ hybridization, that in the adult rat, PPARa is expressed in cells with high catabolic rates of fatty acids and high peroxisome-dependent activities (hepatocytes, cardiomyocytes, proximal tubules of kidney, intestinal mucosa). PPARb is expressed ubiquitously and is abundant in most tissues, whereas PPARg is restricted mainly to adipose tissue, with some expression also in parts of the immune system, the retina, and other organs in trace amounts (25). The localization of PPARa and PPARg gene transcripts and proteins and the nature of their target genes indicates that they play roles in fatty acid catabolism for PPARa, on the one hand, and adipogenesis and lipid storage for PPARg, on the other hand (see Ref. 1 for a review). In contrast, however, the role of the ubiquitously expressed PPARb remains elusive. As the ubiquitous expression of PPARb in the adult rat did not provide clear information as to its roles, developmental expression of this isotype was analyzed, with the goal of unraveling differential patterns of expression that would implicate PPARb in specific events. Developmental patterns of expression of PPARa and PPARg were also investigated to further understand their roles in the embryo. Previous reports of Northern blot analyses in Xenopus and mice showed that PPARb is expressed early and throughout development, whereas PPARa and PPARg appear only later in relatively high amounts (3, 7). However, these studies did provide only limited information, as the distribution within the embryo could not be resolved by the approach used. It is precisely to answer this question that analysis of the differential tissular expression of PPARs during embryonic development of the rat was undertaken by in situ hybridization. Rat embryos were studied using specific probes for rat PPARa, PPARb, and PPARg (25). Embryonic days (E) E8.5, E11.5, E13.5, E15.5, and E18.5 were chosen to cover the most important periods of development: E8.5 for the beginning of organization of the embryo in three layers; E11.5–E15.5 because of the intense differentiation processes that occur in most tissues, particularly in the central nervous system (CNS); and E18.5 because it represents a stage at which many tissues are already expressing specific functions that can be compared with those found in adulthood. Our results show that PPARa and PPARg start to be expressed only late in Received December 2, 1997. Address all correspondence and requests for reprints to: Dr. Walter Wahli, Institut de Biologie Animale, Bâtiment de Biologie, Université de Lausanne, CH-1015 Lausanne, Switzerland. E-mail: walter.wahli@ iba.unil.ch. * This work was supported by the Etat de Vaud and the Swiss National Science Foundation. † Present address: Laboratoire de Chimie Clinique, Centre Hospitalier Universitaire Vaudois, 1011-Lausanne, Suisse. 0013-7227/98/$03.00/0 Vol. 139, No. 6 Endocrinology Printed in U.S.A. Copyright © 1998 by The Endocrine Society