Becoming fat.

Most people do not wish to become fat, for cosmetic as well as medical reasons. Despite this, there is an international epidemic of obesity fueled by sedentary lifestyles and high caloric consumption among people living in industrialized societies. Obesity is characterized by excess adipose tissue, and rational intervention requires an understanding of adipocyte genes, development, and function. The peroxisome proliferator activated receptor (PPAR ), a member of the large family of nuclear hormone receptors, has received enormous attention as its role has emerged in the formation of adipose tissue, as well in the pathogenesis and treatment of diabetes, cardiovascular disease, and cancer (Kersten et al. 2000). In this issue of Genes & Development, Rosen et al. (2002) and Ren et al. (2002) provide answers to two fundamental questions regarding the role of PPAR in the making of a fat cell. Shortly after its initial description as an orphan receptor related to PPAR (Chen et al. 1993; Kliewer et al. 1994), PPAR was found to be particularly abundant in adipose tissue and induced during adipocyte differentiation (Chawla et al. 1994; Tontonoz et al. 1994a). PPAR has since been shown to be sufficient (Tontonoz et al. 1994b) as well as necessary (Barak et al. 1999; Rosen et al. 1999) for adipocyte differentiation. A variety of adipocyte genes are transcriptional targets of PPAR (Auwerx 1999). PPAR ligands, most notably the thiazolidinedione (TZD) class, ameliorate insulin resistance and represent exciting new therapies for type 2 diabetes. This effect of TZDs is likely to be multifactorial, including numerous effects on adipocyte gene expression that lead to altered secretion of adipocyte proteins and fatty acids (Olefsky and Saltiel 2000). In addition to PPAR , the bZip-containing C/EBP transcription factors have established roles in adipogenesis (Loftus and Lane 1997). C/EBP and C/EBP are transiently increased early in adipogenesis (Cao et al. 1991). When constitutively expressed, these factors are sufficient to induce adipocyte differentiation (Yeh et al. 1995), in part owing to induction of PPAR (Wu et al. 1995; Schwarz et al. 1997). C/EBP is induced later. Like PPAR , expression of C/EBP is sustained in the mature adipocytes (Fig. 1A; Birkenmeier et al. 1989; Christy et al. 1989). C/EBP has been shown to be critical for adipogenesis (Freytag et al. 1994; Lin and Lane 1994), and C/EBP and PPAR positively regulate each other’s expression (Shao and Lazar 1997; Hamm et al. 1999). However, previous studies have shown that PPAR can induce adipogenesis in the absence of C/EBP (Fig. 1B; Hamm et al. 1999; Wu et al. 1999). Until now it was unknown whether C/EBP could induce adipogenesis in the absence of PPAR . This is the fundamental question addressed by Rosen et al. (2002), who mutated the PPAR gene in mouse embryonic stem cells, which were used to generate embryonic fibroblasts (MEFs) incapable of expressing PPAR . Normal MEFs can be induced to differentiate into adipocytes, and the PPAR null cells allowed Rosen and colleagues to spotlight the role of PPAR in the hierarchy of adipogenic transcription factors. Their study shows that ectopic expression of C/EBP could not rescue the failure of PPAR null MEFs to differentiate into adipocytes (Fig. 1C). Therefore, rather than being an equal codirector of the adipocyte differentiation program, PPAR has a leading role in the adipogenic hierarchy. C/EBP undoubtedly plays a supporting role in maintaining specific aspects of the adipocyte phenotype, including insulin sensitivity (Hamm et al. 1999; Wu et al. 1999) and lipid accumulation (Wang et al. 1995). The dominance of PPAR also sheds light on the mechanism of lipoatrophy in mice expressing a dominant-negative bZip polypeptide from an adipocyte-specific promoter (Moitra et al. 1998). In this setting, loss of function of all C/EBP proteins most likely interferes with adipocyte differentiation by blocking the induction of PPAR . There are two main isoforms of PPAR : PPAR 1 and PPAR 2 (Fig. 2A). These are generated from a single gene by differential promoter usage. PPAR 1 protein is the translation product of PPAR 1 and PPAR 3 mRNAs, which differ only in their 5 untranslated regions (Fajas et al. 1998). A distinct mRNA encodes PPAR 2 (Tontonoz et al. 1994a). PPAR 2 contains an additional 31 amino acids at its amino terminus, after which it is completely identical to PPAR 1. The amino terminus of PPAR functions as a ligand-independent transcriptional activation domain (Adams et al. 1997). The activation function of the extended amino terminus of PPAR 2 is somewhat more potent than that of PPAR 1, and its activity is affected by insulin (Werman et al. 1997). An amino-terminal serine that is phosphorylated by MAP E-MAIL lazar@mail.med.upenn.edu; FAX (215) 898-5408. Article and publication are at http://www.genesdev. org/cgi/doi/10.1101/ gad.964002.