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...

We show here that the α, β, and γ isotypes of peroxisome proliferator–activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARα and β expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARα, β, and γ mutant mice, we demonstrate that PPARα and β are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARα is mainly involved in the early inflammation phase of the healing, whereas PPARβ is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARβ mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARα and β in adult mouse epidermal repair.

The immediate response to skin injury is the release of inflammatory signals. It is shown here, by use of cultures of primary keratinocytes from wild-type and PPAR␤/␦ −/− mice, that such signals including TNF-␣ and IFN-␥, induce keratinocyte differentiation. This cytokine-dependent cell differentiation pathway requires up-regulation of the PPAR␤/␦ gene via the stress-associated kinase cascade, which targets an AP-1 site in the PPAR␤/␦ promoter. In addition, the pro-inflammatory cytokines also initiate the production of endogenous PPAR␤/␦ ligands, which are essential for PPAR␤/␦ activation and action. Activated PPAR␤/␦ regulates the expression of genes associated with apoptosis resulting in an increased resistance of cultured keratinocytes to cell death. This effect is also observed in vivo during wound healing after an injury, as shown in dorsal skin of PPAR␤/␦ +/+ and PPAR␤/␦ +/− mice.[ Peroxisome proliferator-activated receptors (PPARs), which control many cellular and metabolic processes, are members of the superfamily of ligand-inducible transcription factors known as nuclear receptors. Three isotypes called PPAR␣ (NR1C1), PPAR␤/␦ (NR1C2), and PPAR␥ (NR1C3) (Nuclear Receptors Nomenclature Committee 1999) have been identified in vertebrates. They display differential tissue distribution, suggesting that each of them fulfills specific functions. PPAR␣ and PPAR␥ play important roles in lipid homeostasis and in inflammation (Desvergne and Wahli 1999). In contrast, the exact functions of PPAR␤ remain an enigma. Although fatty acids can bind and activate PPAR␤, studies on this isotype have so far been impeded by the lack of information about the nature of its physiological ligands and by its remarkably broad tissue distribution. Recently however, PPAR␤ was implicated in reverse cholesterol transport (Oliver et al. 2001), in oligodendrocyte maturation and in membrane sheet formation (Saluja et al. 2001). In addition, PPARs may play an important role in skin development, as PPAR␣ ligands can accelerate fetal rat epidermal development (Hanley et al. 1998). In epidermis, the three PPAR isotypes are expressed during development, but their levels decrease to become undetectable in the interfollicular keratinocytes 5-9 d after birth (Michalik et al. 2001). However, the expression of both PPAR␣ and PPAR␤ is reactivated upon proliferative stimuli, such as treatment with the phorbol ester TPA or hair plucking and at the wound edges after skin injury. Although PPAR␤ −/− and PPAR␤ +/− mice are not affected by apparent skin defects, they display an increased hyperplasic response to TPA treatment (Peters et al. 2000;Michalik et al. 2001). More interestingly, wound closure is delayed in PPAR␤ +/− mice as compared with wild-type animals (Michalik et al. 2001). Taken together, these observations suggest that PPAR␤ may play an important role in skin, particularly in stress situations.The epidermis in which keratinocyte is the predominant cell type is characterized by a lifelong polarized pattern of epithelial growth and cell differ...

The use of nanomaterials has raised safety concerns, as their small size facilitates accumulation in and interaction with biological tissues. Here we show that exposure of endothelial cells to TiO 2 nanomaterials causes endothelial cell leakiness. This effect is caused by the physical interaction between TiO 2 nanomaterials and endothelial cells' adherens junction protein VE-cadherin. As a result, VE-cadherin is phosphorylated at intracellular residues (Y658 and Y731), and the interaction between VE-cadherin and p120 as well as b-catenin is lost. The resulting signalling cascade promotes actin remodelling, as well as internalization and degradation of VE-cadherin. We show that injections of TiO 2 nanomaterials cause leakiness of subcutaneous blood vessels in mice and, in a melanoma-lung metastasis mouse model, increase the number of pulmonary metastases. Our findings uncover a novel non-receptor-mediated mechanism by which nanomaterials trigger intracellular signalling cascades via specific interaction with VE-cadherin, resulting in nanomaterial-induced endothelial cell leakiness.