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...

Phytanic acid, a metabolite of the chlorophyll molecule, is part of the human diet and is present in normal human serum at low micromolar concentrations. It was previously shown to be a ligand of the 9-cis-retinoic acid receptor and peroxisome proliferator-activated receptor (PPAR) a. PPAR agonists are widely used in the treatment of type 2 diabetes. Here, we report that phytanic acid is not only a transactivator of PPARa, but it also acts via PPARb and PPARg in CV-1 cells that have been cotransfected with the respective full-length receptor and an acyl-CoA oxidase-PPAR-responsive element-luciferase construct. We observed that, in contrast to other fatty acids, phytanic acid at physiological concentrations enhances uptake of 2-deoxy-D-glucose in rat primary hepatocytes. This result could be explained by the increase in mRNA expression of glucose transporters-1 and -2 and glucokinase, as determined by quantitative real-time reverse transcriptase-polymerase chain reaction. Compared with the PPARg-specific agonist ciglitazone, phytanic acid exerts only minor effects on the differentiation of C3H10T1/2 cells into mature adipocytes. These results clearly demonstrate that phytanic acid acts via different PPAR isoforms to modulate expression of genes involved in glucose metabolism, thus suggesting a potential role of phytanic acid in the management of insulin resistance.

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The calcitonin (CT)-like (CL) receptor is a CT generelated peptide (CGRP) receptor or an adrenomedullin (AM) receptor when co-expressed with receptor-activity-modifying proteins (RAMP) 1 or 2, respectively. The CL receptor shows 57% overall sequence identity with the CT receptor, but the homology is much lower in the extreme N-terminus. An N-terminal deletion mutant of the human (h) CL receptor (v v18-hCL) and a chimeric receptor consisting of the N-terminal amino acids of the porcine (p) CT receptor fused to the v v18-hCL receptor (pCT^hCL) were therefore analyzed. The v v18-hCL receptor function was abolished when co-expressed with RAMP1 or -2. The pCT^hCL receptor was a fully functional CGRP receptor when co-expressed with RAMP1, but the RAMP2-dependent AM receptor function was impaired. Limited sequence similarities in the N-terminus of the pCT and the hCL receptors rescue CGRP but not AM receptor binding and signalling.