Proteins secreted from adipose tissue are increasingly recognized to play an important role in the regulation of glucose metabolism. However, much less is known about their effect on lipid metabolism. The fasting-induced adipose factor (FIAF/ angiopoietin-like protein 4/peroxisome proliferator-activated receptor ␥ angiopoietinrelated protein) was previously identified as a target of hypolipidemic fibrate drugs and insulin-sensitizing thiazolidinediones. Using transgenic mice that mildly overexpress FIAF in peripheral tissues we show that FIAF is an extremely powerful regulator of lipid metabolism and adiposity. FIAF overexpression caused a 50% reduction in adipose tissue weight, partly by stimulating fatty acid oxidation and uncoupling in fat. In addition, FIAF overexpression increased plasma levels of triglycerides, free fatty acids, glycerol, total cholesterol, and high density lipoprotein (HDL)-cholesterol. Functional tests indicated that FIAF overexpression severely impaired plasma triglyceride clearance but had no effect on very low density lipoprotein production. The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet. Remarkably, in mice the full-length form of FIAF was physically associated with HDL, whereas truncated FIAF was associated with low density lipoprotein. In human both fulllength and truncated FIAF were associated with HDL. The composite data suggest that via physical association with plasma lipoproteins, FIAF acts as a powerful signal from fat and other tissues to prevent fat storage and stimulate fat mobilization. Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia.Obesity and associated diabetes mellitus type 2 have become major health concerns throughout the world. These ailments are intimately linked as excess weight greatly increases the likelihood of developing diabetes. Obesity also increases the risk for other clinical abnormalities such as hypertension and dyslipidemia. Although the positive association between obesity and several co-morbidities has been well established at the epidemiological level, the mechanisms behind these associations are much less clear. Much attention has been given to the role of plasma free fatty acids (FFAs), 3 which are elevated in the obese and able to disrupt cellular metabolism in several organs. However, it also has become evident that a variety of hormonal factors produced by adipose tissue can greatly affect organ functioning, especially at the metabolic and immunological levels (1). Indeed, these so-called adipocytokines or adipokines are now known to affect diverse biological processes, ranging from energy intake, insulin sensitivity, and hepatic glucose production, to reproductive and immunological function (2-5). Whereas the effects of adipocytokines on glucose homeostasis are becoming increasingly transpare...

The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA was up-regulated by peroxisome proliferator-activated receptor ␣ (PPAR␣) and PPAR␤/␦ agonists in rat and human hepatoma cell lines and by PPAR␥ and PPAR␤/␦ agonists in mouse and human adipocytes. Transactivation, chromatin immunoprecipitation, and gel shift experiments identified a functional PPAR response element within intron 3 of the FIAF gene. At the protein level, in human and mouse blood plasma, FIAF was found to be present both as the native protein and in a truncated form. Differentiation of mouse 3T3-L1 adipocytes was associated with the production of truncated FIAF, whereas in human white adipose tissue and SGBS adipocytes, only native FIAF could be detected. Interestingly, truncated FIAF was produced by human liver. Treatment with fenofibrate, a potent PPAR␣ agonist, markedly increased plasma levels of truncated FIAF, but not native FIAF, in humans. Levels of both truncated and native FIAF showed marked interindividual variation but were not associated with body mass index and were not influenced by prolonged semistarvation. Together, these data suggest that FIAF, similar to other adipocytokines such as adiponectin, may partially exert its function via a truncated form.

PPARs (peroxisome-proliferator-activated receptors) alpha, beta/delta and gamma are a group of transcription factors that are involved in numerous processes, including lipid metabolism and adipogenesis. By comparing liver mRNAs of wild-type and PPARalpha-null mice using microarrays, a novel putative target gene of PPARalpha, G0S2 (G0/G1 switch gene 2), was identified. Hepatic expression of G0S2 was up-regulated by fasting and by the PPARalpha agonist Wy14643 in a PPARalpha-dependent manner. Surprisingly, the G0S2 mRNA level was highest in brown and white adipose tissue and was greatly up-regulated during mouse 3T3-L1 and human SGBS (Simpson-Golabi-Behmel syndrome) adipogenesis. Transactivation, gel shift and chromatin immunoprecipitation assays indicated that G0S2 is a direct PPARgamma and probable PPARalpha target gene with a functional PPRE (PPAR-responsive element) in its promoter. Up-regulation of G0S2 mRNA seemed to be specific for adipogenesis, and was not observed during osteogenesis or myogenesis. In 3T3-L1 fibroblasts, expression of G0S2 was associated with growth arrest, which is required for 3T3-L1 adipogenesis. Together, these data indicate that G0S2 is a novel target gene of PPARs that may be involved in adipocyte differentiation.

SummaryPeroxisome proliferators-activated receptor (PPAR)α is a nuclear receptor activated by natural ligands such as fatty acids as well as by synthetic ligands such as fibrates currently used to treat dyslipidemia. PPARα regulates the expression of genes encoding proteins that are involved in lipid metabolism, fatty acid oxidation and glucose homeostasis, thereby improving markers for atherosclerosis and insulin resistance. In addition, PPARα exerts anti-inflammatory effects both in the vascular wall and the liver. Here we provide an overview of the mechanisms through which PPARα affects the initiation and progression of atherosclerosis, with emphasis on the modulation of atherosclerosis-associated inflammatory responses. PPARα activation interferes with early steps in angiogenesis by reducing leukocyte adhesion to activated endothelial cells of the arterial vessel wall and inhibiting subsequent transendothelial leukocyte migration. In later stages of atherosclerosis, evidence suggests activation of PPARα inhibits the formation of macrophage foam cells by regulating expression of genes involved in reverse cholesterol transport, formation of reactive oxygen species (ROS), and associated lipoprotein oxidative modification among others. Furthermore, PPARα may increase the stability of atherosclerotic plaques and limit plaque thrombogenicity. These various effects may be linked to the generation of PPARα ligands by endogenous mechanisms of lipoprotein metabolism. In spite of this dataset, other reports implicate PPARα in responses such as hypertension and diabetic cardiomyopathy. Although some clinical trials data with fibrates suggest that fibrates may decrease cardiovascular events, other studies have been less clear, at least in the presence of concomitant statin therapy. Independent of the clinical effects of currently used purported PPARα agonists, extensive data establishes the importance of PPARα in the transcriptional regulation of lipid metabolism, atherosclerosis and inflammation.

Peroxisome proliferator-activated receptors (PPARs) as ligand-activated nuclear receptors involved in the transcriptional regulation of lipid metabolism, energy balance, inflammation, and atherosclerosis are at the intersection of key pathways involved in the pathogenesis of diabetes and cardiovascular disease. Synthetic PPAR agonists like fibrates (PPAR-a) and thiazolidinediones (PPAR-c) are in therapeutic use to treat dyslipidaemia and diabetes. Despite strong encouraging in vitro, animal model, and human surrogate marker studies with these agents, recent prospective clinical cardiovascular trials have yielded mixed results, perhaps explained by concomitant drug use, study design, or a lack of efficacy of these agents on cardiovascular disease (independent of their current metabolic indications). The use of PPAR agents has also been limited by untoward effects. An alternative strategy to PPAR therapeutics is better understanding PPAR biology, the nature of natural PPAR agonists, and how these molecules are generated. Such insight might also provide valuable information about pathways that protect against the metabolic problems for which PPAR agents are currently indicated. This approach underscores the important distinction between the effects of synthetic PPAR agonists and the unequivocal biologic role of PPARs as key transcriptional regulators of metabolic and inflammatory pathways relevant to diabetes and atherosclerosis.

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BackgroundArsenic (As) exposure is a significant worldwide environmental health concern. Chronic exposure via contaminated drinking water has been associated with an increased incidence of a number of diseases, including reproductive and developmental effects. The goal of this study was to identify adverse outcomes in a mouse model of early life exposure to low-dose drinking water As (10 ppb, current U.S. EPA Maximum Contaminant Level).Methodology and FindingsC57B6/J pups were exposed to 10 ppb As, via the dam in her drinking water, either in utero and/or during the postnatal period. Birth outcomes, the growth of the F1 offspring, and health of the dams were assessed by a variety of measurements. Birth outcomes including litter weight, number of pups, and gestational length were unaffected. However, exposure during the in utero and postnatal period resulted in significant growth deficits in the offspring after birth, which was principally a result of decreased nutrients in the dam's breast milk. Cross-fostering of the pups reversed the growth deficit. Arsenic exposed dams displayed altered liver and breast milk triglyceride levels and serum profiles during pregnancy and lactation. The growth deficits in the F1 offspring resolved following separation from the dam and cessation of exposure in male mice, but did not resolve in female mice up to six weeks of age.Conclusions/SignificanceExposure to As at the current U.S. drinking water standard during critical windows of development induces a number of adverse health outcomes for both the dam and offspring. Such effects may contribute to the increased disease risks observed in human populations.

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