Abstract--The three peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homology with all members of the superfamily, particularly in the DNA-binding domain and ligand-and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPAR␣ is expressed at high levels in organs with significant catabolism of fatty acids. PPAR␤/␦ has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPAR␥ is expressed as two isoforms, of which PPAR␥2 is found at high levels in the adipose tissues, whereas PPAR␥1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a peroxisome proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compounds was identified as PPAR ligands. Among the synthetic ligands, the lipidlowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPAR␣ and PPAR␥ agonists, respectively, which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors exerting several functions in development and metabolism. The physiological functions of PPARdelta remain elusive. By using a CRE-Lox recombination approach, we generated an animal model for muscle-specific PPARdelta overexpression to investigate the role of PPARdelta in this tissue. Muscle-specific PPARdelta overexpression results in a profound change in fiber composition due to hyperplasia and/or shift to more oxidative fiber and, as a consequence, leads to the increase of both enzymatic activities and genes implicated in oxidative metabolism. These changes in muscle are accompanied by a reduction of body fat mass, mainly due to a large reduction of adipose cell size. Furthermore, we demonstrate that endurance exercise promotes an accumulation of PPARdelta protein in muscle of wild-type animals. Collectively, these results suggest that PPARdelta plays an important role in muscle development and adaptive response to environmental changes, such as training exercise. They strongly support the idea that activation of PPARdelta could be beneficial in prevention of metabolic disorders, such as obesity or type 2 diabetes.

Both in animals and humans, before or after birth, angiogenesis appears to be closely coordinated in time and space with the formation of fat cell clusters. Monobutyrin, a novel fat-specific angiogenesis factor, may play a role in this process. The potential to acquire new fat cells appears to be permanent throughout life in both animals and humans, as revealed by in vitro experiments. Considerable evidence now supports the view that BAT and WAT are distinct organs; in addition, the existence of distinct BAT precursor cells is demonstrated by their unique ability to express the UCP gene. In bovine and ovine, the transformation of BAT into WAT is strongly suggested by the rapid disappearance after birth of UCP from the various BAT depots. Despite the initial cell heterogeneity of the stromal-vascular fraction, cultured stromal-vascular cells of adipose tissue are adipose precursor cells that show varying capacities for replication and differentiation, according to age and fat depot. Studies of adipose cell differentiation in vitro correspond to the sequence: adipoblast (unipotential cells)----commitment preadipose cell (preadipocyte)----terminal differentiation immature adipose cell----terminal differentiation mature adipose cell (adipocyte). Cell commitment is triggered by growth arrest and characterized by the expression of early markers (A2COL6/pOb24; clone 5; LPL), whereas only terminal differentiation of preadipocytes requires the presence of various hormones. Multiple signaling pathways have been characterized and shown to cooperate in the process of terminal differentiation. The concept that adipose cells behave as secretory cells is now emerging from in vitro data, since secretion of various proteins (LPL, adipsin, CETP) and important metabolites (fatty acids, monobutyrin, androgens, estrogens, prostaglandins) takes place both constitutively and upon hormonal stimulation. This suggests that adipose tissue participates more directly than previously thought in metabolic activities and energy balance.

Exposure of preadipocytes to long chain fatty acids induces expression of several gene markers of adipocyte differentiation. This report describes the cloning, from a preadipocyte library, of a cDNA encoding a fatty acid-activated receptor, FAAR. The cDNA had the characteristics and ligand-binding domains of nuclear hormone receptors and encoded a 440 amino acid protein related to peroxisome proliferator-activated receptors, PPAR. The deduced protein sequence was 88% homologous to that of hNUC I, isolated from human osteosarcoma cells. FAAR mRNA was abundant in adipose tissue, intestine, brain, heart, and skeletal muscles and less abundant in kidney, liver, testis, and spleen. The mRNA was undetectable in growing Ob1771 and 3T3-F442A preadipocytes, was strongly induced early during differentiation, and was increased by fatty acid. Transcription assays using hybrid receptor showed strong stimulation by fatty acid and weaker induction by fibrates. Transfection of 3T3-C2 fibroblasts, with a FAAR expression vector, conferred fatty acid inducibility of the adipocyte lipid-binding protein and the fatty acid transporter. Transcriptional induction of these genes exhibited inducer specificity identical to that described in preadipocytes. In summary, the data indicate that FAAR is likely a mediator of fatty acid transcriptional effects in preadipocytes.

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The peroxisome proliferator-activated receptors, PPARα, PPARβ, and PPARγ, are a family of transcription factors activated by a diversity of molecules including fatty acids and fatty acid metabolites. PPARs regulate the transcription of a large variety of genes implicated in metabolism, inflammation, proliferation, and differentiation in different cell types. These transcriptional regulations involve both direct transactivation and interaction with other transcriptional regulatory pathways. The functions of PPARα and PPARγ have been extensively documented mainly because these isoforms are activated by molecules clinically used as hypolipidemic and antidiabetic compounds. The physiological functions of PPARβ remained for a while less investigated, but the finding that specific synthetic agonists exert beneficial actions in obese subjects uplifted the studies aimed to elucidate the roles of this PPAR isoform. Intensive work based on pharmacological and genetic approaches and on the use of both in vitro and in vivo models has considerably improved our knowledge on the physiological roles of PPARβ in various cell types. This review will summarize the accumulated evidence for the implication of PPARβ in the regulation of development, metabolism, and inflammation in several tissues, including skeletal muscle, heart, skin, and intestine. Some of these findings indicate that pharmacological activation of PPARβ could be envisioned as a therapeutic option for the correction of metabolic disorders and a variety of inflammatory conditions. However, other experimental data suggesting that activation of PPARβ could result in serious adverse effects, such as carcinogenesis and psoriasis, raise concerns about the clinical use of potent PPARβ agonists.

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