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 wild-type 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 wild-type 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.

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 PPARβ/δ^−/− mice, that such signals including TNF-α and IFN-γ, induce keratinocyte differentiation. This cytokine-dependent cell differentiation pathway requires up-regulation of the PPARβ/δ gene via the stress-associated kinase cascade, which targets an AP-1 site in thePPARβ/δ promoter. In addition, the pro-inflammatory cytokines also initiate the production of endogenous PPARβ/δ ligands, which are essential for PPARβ/δ activation and action. Activated PPARβ/δ 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 PPARβ/δ^+/+ and PPARβ/δ^+/− mice.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that can be activated by fatty acids and peroxisome proliferators. The PPARα subtype mediates the pleiotropic effects of these activators in liver and regulates several target genes involved in fatty acid catabolism. In primary hepatocytes cultured in vitro, the PPARα gene is regulated at the transcriptional level by glucocorticoids. We investigated if this hormonal regulation also occurs in the whole animal in physiological situations leading to increased plasma corticosterone levels in rats. We show here that an immobilization stress is a potent and rapid stimulator of PPARα expression in liver but not in hippocampus. The injection of the synthetic glucocorticoid dexamethasone into adult rats produces a similar increase in PPARα expression in liver, whereas the administration of the antiglucocorticoid RU 486 inhibits the stress-dependent stimulation. We conclude that glucocorticoids are major mediators of the stress response. Consistent with this hormonal regulation, hepatic PPARα mRNA and protein levels follow a diurnal rhythm, which parallels that of circulating corticosterone. To test the effects of variations in PPARα expression on PPARα target gene activity, high glucocorticoid-dependent PPARα expression was mimicked in cultured primary hepatocytes. Under these conditions, hormonal stimulation of receptor expression synergizes with receptor activation by WY-14,643 to induce the expression of the PPARα target gene acyl-CoA oxidase. Together, these results show that regulation of the PPARα expression levels efficiently modulates PPAR activator signaling and thus may affect downstream metabolic pathways involved in lipid homeostasis.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate the expression of many genes involved in lipid metabolism. The biological roles of PPARα and PPARγ are relatively well understood, but little is known about the function of PPARβ. To address this question, and because PPARβ is expressed to a high level in the developing brain, we used reaggregated brain cell cultures prepared from dissociated fetal rat telencephalon as experimental model. In these primary cultures, the fetal cells initially form random aggregates, which progressively acquire a tissue-specific pattern resembling that of the brain. PPARs are differentially expressed in these aggregates, with PPARβ being the prevalent isotype. PPARα is present at a very low level, and PPARγ is absent. Cell type-specific expression analyses revealed that PPARβ is ubiquitous and most abundant in some neurons, whereas PPARα is predominantly astrocytic. We chose acyl-CoA synthetases (ACSs) 1, 2, and 3 as potential target genes of PPARβ and first analyzed their temporal and cell type-specific pattern. This analysis indicated that ACS2 and PPARβ mRNAs have overlapping expression patterns, thus designating the ACS2 gene as a putative target of PPARβ. Using a selective PPARβ activator, we found that the ACS2 gene is transcriptionally regulated by PPARβ, demonstrating a role for PPARβ in brain lipid metabolism.