Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor α (PPARα) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARα may be involved in the transcriptional response to fasting. To investigate this possibility, PPARα-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wildtype mice. PPARα-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARα-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARα mRNA is induced during fasting in wildtype mice. The data indicate that PPARα plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARα stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues. J. Clin. Invest. 103:1489-1498 (1999).adipose tissue (BAT) and the liver, and to a lesser extent in the kidneys, skeletal muscle, and heart (10). Of the 3 isotypes, PPARα has been the best characterized, a fortunate consequence of the availability of PPARα-null mice (16). Studies with these mice have demonstrated that PPARα controls the expression of numerous genes related to lipid metabolism in the liver, including genes involved in mitochondrial β-oxidation, peroxisomal β-oxidation, fatty acid uptake and/or binding, and lipoprotein assembly and transport (17)(18)(19). Several functional consequences of lowered gene expression levels were observed: PPARα-null mice are refractory to peroxisome proliferators, and male mice appeared to be overly sensitive to etomoxir, an inhibitor of carnitine palmitoyltransferase I (CPTI) (16,20). A striking metabolic defect was observed in aged (8-month-old) PPARα-null mice, characterized by a sexually dimorphic dyslipidemia with pronounced adiposity in females and steatosis in males (21). Despite this great expansion of our understanding of the function of PPARα, what remains unclear is when and how, in an intact organism, the PPARα signaling pathways are triggered, and how this specifically affects lipid and carbohydrate metabolism.One physiological condition during which PPARα-dependent signaling should become challenged is fasting, because (a) huge amounts of fatty acids are delivered to the liver to be oxidized; (b) once taken up, fatty acids have to be delivered to the mitochondria for oxidation; and (c) β-oxidation is accelerated in conjunction with increased synthesis of ketone bodies.A second physiological stimulus that may challenge t...

Peroxisome proliferator-activated receptors (PPARs) ␣ and ␥ are key regulators of lipid homeostasis and are activated by a structurally diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While thiazolidinediones and 15-deoxy-⌬ 12,14 -prostaglandin J 2 have been shown to bind to PPAR␥, it has remained unclear whether other activators mediate their effects through direct interactions with the PPARs or via indirect mechanisms. Here, we describe a novel fibrate, designated GW2331, that is a highaffinity ligand for both PPAR␣ and PPAR␥. Using GW2331 as a radioligand in competition binding assays, we show that certain mono-and polyunsaturated fatty acids bind directly to PPAR␣ and PPAR␥ at physiological concentrations, and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-⌬ 12,14 -prostaglandin J 2 can function as subtypeselective ligands for PPAR␣ and PPAR␥, respectively. These data provide evidence that PPARs serve as physiological sensors of lipid levels and suggest a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved in lipid metabolism and also play a role in adipocyte differentiation. We present the expression patterns of the PPAR subtypes in the adult rat, determined by in situ hybridization using specific probes for PPAR-alpha, -beta and -gamma, and by immunohistochemistry using a polyclonal antibody that recognizes the three rat PPAR subtypes. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, with relative levels varying between them from one cell type to the other. PPAR-alpha is highly expressed in hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPAR-beta is expressed ubiquitously and often at higher levels than PPAR-alpha and -gamma. PPAR-gamma is expressed predominantly in adipose tissue and the immune system. Our results suggest new potential directions to investigate the functions of the different PPAR subtypes.

Inflammation is a local immune response to 'foreign' molecules, infection and injury. Leukotriene B4, a potent chemotactic agent that initiates, coordinates, sustains and amplifies the inflammatory response, is shown to be an activating ligand for the transcription factor PPARalpha. Because PPARalpha regulates the oxidative degradation of fatty acids and their derivatives, like this lipid mediator, a feedback mechanism is proposed that controls the duration of an inflammatory response and the clearance of leukotriene B4 in the liver. Thus PPARalpha offers a new route to the development of anti- or pro-inflammatory reagents.

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.

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Fasting is associated with significant changes in nutrient metabolism, many of which are governed by transcription factors that regulate the expression of ratelimiting enzymes. One factor that plays an important role in the metabolic response to fasting is the peroxisome proliferator-activated receptor ␣ (PPAR␣). To gain more insight into the role of PPAR␣ during fasting, and into the regulation of metabolism during fasting in general, a search for unknown PPAR␣ target genes was performed. Using subtractive hybridization (SABRE) comparing liver mRNA from wild-type and PPAR␣ null mice, we isolated a novel PPAR␣ target gene, encoding the secreted protein FIAF (for fasting induced adipose factor), that belongs to the family of fibrinogen/angiopoietin-like proteins. FIAF is predominantly expressed in adipose tissue and is strongly up-regulated by fasting in white adipose tissue and liver. Moreover, FIAF mRNA is decreased in white adipose tissue of PPAR␥ ؉/؊ mice. FIAF protein can be detected in various tissues and in blood plasma, suggesting that FIAF has an endocrine function. Its plasma abundance is increased by fasting and decreased by chronic high fat feeding. The data suggest that FIAF represents a novel endocrine signal involved in the regulation of metabolism, especially under fasting conditions. In many developed and developing countries, the prevalence of diabetes, particularly type II diabetes, is increasing at an alarming rate. Despite intensive research over the past decades, the knowledge about the metabolic derangements precipitating to and accompanying type II diabetes remains fragmentary. One factor that has limited progress of diabetes research has been a lack of clear understanding of the regulation of nutrient metabolism under normal, non-diabetic conditions. Indeed, much still needs to be learned about the genetics of metabolism during various physiological states, such as fasting.Fasting can be described as a state when food intake has been arrested for a significant amount of time. The absence of energy entering the body evokes a complex physiological response aimed at maintaining whole body homeostasis. A critical event in the fasting response is the liberation of fatty acids from the adipose tissue and their preferential use as an energy substrate in tissues such as skeletal muscle and liver. The metabolic adaptations accompanying fasting are governed by numerous endocrine and cellular factors. Fasting results in pronounced changes in the plasma concentrations of important metabolic hormones such as insulin, glucocorticoids, leptin, and glucagon. In addition, fasting causes altered expression levels of important transcription factors, such as sterol response element-binding protein (1), c-Myc (2), and peroxisome proliferator-activated receptor ␣ (PPAR␣) 1 (3), directing specific changes in the expression of metabolic enzymes. We and others (3, 4) have recently shown the important role of PPAR␣ in the fasting response. By stimulating the oxidation of fatty acids in liver, this transcription fa...

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