The three isotypes of peroxisome proliferator-activated receptors (PPARs), PPARalpha, beta/delta and gamma, are ligand-inducible transcription factors that belong to the nuclear hormone receptor family. PPARs are implicated in the control of inflammatory responses and in energy homeostasis and thus, can be defined as metabolic and anti-inflammatory transcription factors. They exert their anti-inflammatory effects by inhibiting the induction of pro-inflammatory cytokines, adhesion molecules and extracellular matrix proteins or by stimulating the production of anti-inflammatory molecules. Furthermore, PPARs modulate the proliferation, differentiation and survival of immune cells including macrophages, B cells and T cells. This review discusses the molecular mechanisms by which PPARs and their ligands modulate the inflammatory response. In addition, it presents recent developments implicating PPAR specific ligands in potential treatments of inflammation-related diseases, such as atherosclerosis, inflammatory bowel diseases, Parkinson's and Alzheimer's diseases.
Dehydroepiandrosterone (DHEA) exerts beneficial effects on blood glucose levels and insulin sensitivity in obese rodents and humans, resembling the effects of peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands and opposing those of glucocorticoids; however, the underlying mechanisms remain unclear. Glucocorticoids are reactivated locally by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which is currently considered as a promising target for the treatment of obesity and diabetes. Using differentiated 3T3-L1 adipocytes, we show that DHEA causes downregulation of 11beta-HSD1 and dose-dependent reduction of its oxoreductase activity. The effects of DHEA were comparable with those of the PPARgamma agonist rosiglitazone but not additive. Furthermore, DHEA reduced the expression of hexose-6-phosphate dehydrogenase, which stimulates the oxoreductase activity of 11beta-HSD1. These findings were confirmed in white adipose tissue and in liver from DHEA-treated C57BL/6J mice. Analysis of the transcription factors involved in the DHEA-dependent regulation of 11beta-HSD1 expression revealed a switch in CCAAT/enhancer-binding protein (C/EBP) expression. C/EBPalpha, a potent activator of 11beta-HSD1 gene transcription, was downregulated in 3T3-L1 adipocytes and in liver and adipose tissue of DHEA-treated mice, whereas C/EBPbeta and C/EBPdelta, attenuating the effect of C/EBPalpha, were unchanged or elevated. Our results further suggest a protective effect of DHEA on adipose tissue by upregulating PPARalpha and downregulating leptin, thereby contributing to the reduced expression of 11beta-HSD1. In summary, we provide evidence that some of the anti-diabetic effects of DHEA may be caused through inhibition of the local amplification of glucocorticoids by 11beta-HSD1 in adipose tissue.
Poly(ADP-ribose)polymerase-1 (PARP1) is a chromatin-associated enzyme that was described to affect chromatin compaction. Previous reports suggested a dynamic modulation of the chromatin landscape during adipocyte differentiation. We thus hypothesized that PARP1 plays an important transcriptional role in adipogenesis and metabolism and therefore used adipocyte development and function as a model to elucidate the molecular action of PARP1 in obesity-related diseases. Our results show that PARP1-dependent ADP-ribose polymer (PAR) formation increases during adipocyte development and, at late time points of adipogenesis, is involved in the sustained expression of PPARγ2 and of PPARγ2 target genes. During adipogenesis, PARP1 was recruited to PPARγ2 target genes such as CD36 or aP2 in a PAR-dependent manner. Our results also reveal a PAR-dependent decrease in repressory histone marks (e.g. H3K9me3) and an increase in stimulatory marks (e.g. H3K4me3) at the PPARγ2 promoter, suggesting that PARP1 may exert its regulatory function during adipogenesis by altering histone marks. Interestingly, activation of PARP1 enzymatic activity was prevented with a topoisomerase II inhibitor. These data hint at topoisomerase II-dependent, transient, site-specific double-strand DNA breaks as the cause for poly(ADP)-ribose formation, adipogenic gene expression, and adipocyte function. Together, our study identifies PARP1 as a critical regulator of PPARγ2-dependent gene expression with implications in adipocyte function and obesity-related disease models.
ADP-ribosyltransferase Diphtheria toxin-like 1 [ARTD1; formerly called poly-ADP-ribose polymerase 1 (PARP1)] is a chromatin-associated enzyme involved in regulating metabolic homeostasis. The liver is at the core of glucose and lipid metabolism and is significantly affected by obesity and the metabolic syndrome. Here, we show that when fed a high-fat diet (HFD), mice lacking ARTD1 developed exacerbated hepatic steatosis. ARTD1(-/-) mice had a 19% higher liver weight than wild-type (WT) animals and exhibited a significantly increased serum concentration of cholesterol (38%) and impaired glucose tolerance. In addition, adipocyte function and size were significantly reduced in ARTD1(-/-) mice fed an HFD (7794 μm(2) for WT and 5579 μm(2) for ARTD1(-/-) mice). The significantly reduced adipogenic differentiation of adipose-derived stromal cells (ASCs) isolated from ARTD1(-/-) mice (28 vs. 11% Oil red O-positive cells in WT and ARTD1(-/-) ASCs, respectively) suggested that impaired adipogenesis as the underlying cause for this adipose tissue malfunction. This function of ARTD1 was specific for adipogenesis, since osteogenic differentiation was not affected by the ARTD1 deletion. In summary, we show that ARTD1(-/-) mice fed an HFD display impaired adipogenesis and show exacerbated hepatic steatosis, which can have important implications for nonalcoholic fatty liver disease.
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