Administration of dehydroepiandrosterone (DHEA), a precursor of sex steroid hormones, reduces total and visceral fat mass and elevates adipocytic adiponectin gene expression. The aim of this study is to investigate whether levels of peroxisome proliferator-activated receptors (PPARs) in muscle and t
ranscription of PPAR target genes are affected by long-term DHEA administration or exercise training, and whether altered PPAR levels are associated with circulating adiponectin level in obese rats. After 14 weeks on a high-sucrose diet, obese male Wistar rats were assigned randomly to one of 3 groups: control, DHEA administration (1 mg/kg body weight), or exercise training (treadmill running for 1¿h, 25¿m/min, 5 days/week) for 6 weeks (n=7 for each group). Plasma DHEA and total adiponectin levels in the DHEA-treated and exercise-training groups were significantly higher than those in the obese control group. Additionally, DHEA administration and exercise training significantly increased muscular PPARa and PPARd protein levels, with a concomitant increase in mRNA expression of 3ß-hydroxyacyl-CoA dehydrogenase and cytochrome c oxidase IV, which are target genes of PPARa and PPARd respectively. Moreover, DHEA administration increased these protein and mRNA levels to the same degree as exercise training. Circulating adiponectin level was positively correlated with plasma DHEA and with muscle levels of PPARa and PPARd. These results suggest that in obese rats, secretion of adiponectin due to chronic DHEA administration and exercise training may contribute to an increase in the transcription of genes encoding lipid metabolic enzymes, mediated via elevated expression of PPARa and PPARd in muscle.
Ham SA, etal., J Dermatol Sci. 2015 Dec;80(3):186-95. doi: 10.1016/j.jdermsci.2015.10.005. Epub 2015 Oct 9.
BACKGROUND: The phenotypic changes that accompany differentiation of resident fibroblasts into myofibroblasts are important aspects of the wound healing process. Recent studies showed that peroxisome proliferator-activated receptor (PPAR) delta plays a critical role in wound healing. OBJECTIVE: To d
etermine whether the nuclear receptor PPARdelta can modulate the differentiation of human dermal fibroblasts (HDFs) into myofibroblasts. METHODS: These studies were undertaken in primary HDFs using Western blot analyses, small interfering (si)RNA-mediated gene silencing, reporter gene assays, chromatin immunoprecipitation (ChIP), migration assays, collagen gel contraction assays, and real-time PCR. RESULTS: Activation of PPARdelta by GW501516, a specific ligand of PPARdelta, specifically upregulated the myofibroblast marker alpha-smooth muscle actin (alpha-SMA) in a time- and concentration-dependent manner. This induction was significantly inhibited by the presence of siRNA against PPARdelta, indicating that PPARdelta is involved in myofibroblast transdifferentiation of HDFs. Ligand-activated PPARdelta increased alpha-SMA promoter activity in a dual mode by directly binding a direct repeat-1 (DR1) site in the alpha-SMA promoter, and by inducing expression of transforming growth factor (TGF)-beta, whose downstream effector Smad3 interacts with a Smad-binding element (SBE) in another region of the promoter. Mutations in these cis-elements totally abrogated transcriptional activation of the alpha-SMA gene by the PPARdelta ligand; thus both sites represent novel types of PPARdelta response elements. GW501516-activated PPARdelta also increased the migration and contractile properties of HDFs, as demonstrated by Transwell and collagen lattice contraction assays, respectively. In addition, PPARdelta-mediated upregulation of alpha-SMA was correlated with elevated expression of myofibroblast markers such as collagen I and fibronectin, with a concomitant reduction in expression of the epithelial marker E-cadherin. CONCLUSION: PPARdelta plays pivotal roles in wound healing by promoting fibroblast-to-myofibroblast differentiation via TGF-beta/Smad3 signaling.
Ye HD, etal., Genet Mol Res. 2015 Jun 11;14(2):6350-9. doi: 10.4238/2015.June.11.10.
PPARD encodes peroxisome proliferator-activated re-ceptor delta, which has been shown to play an important role in control-ling lipid metabolism and atherosclerosis. In this case-control study, we explored the relationship between PPARD
PPARD rs2016520 polymorphism and coronary heart disease (CHD) in a Han Chinese population. A to-tal of 657 CHD cases and 640 controls were included in the associa-tion study. rs2016520 polymorphism genotyping was performed using the melting temperature-shift polymerase chain reaction method. The PPARD rs2016520-G allele reduced CHD risk by 17.9% (chi(2) = 5.061, P = 0.025, OR = 0.821, 95%CI = 0.692-0.975). Furthermore, a signifi-cant difference in CHD risk was observed for the PPARD rs2016520 polymorphism in the dominant model (AG + GG vs AA: chi(2) = 4.751, degrees of freedom (df) = 1, P = 0.029, OR = 0.784, 95%CI = 0.631- 0.976). Analysis by age suggested that the G-allele decreased CHD risk by 14.8% in ages greater than 65 years (chi(2) = 4.446, P = 0.035, OR = 0.852, 95%CI = 0.684-1.060). In contrast, meta-analysis of PPARD rs2016520 among 3732 cases and 5042 controls revealed no associa-tion between PPARD rs2016520 and CHD (P = 0.19). We found that the PPARD rs2016520-GG genotype decreased CHD risk in a Han Chinese population. Moreover, we found an association between serum high-density lipoprotein cholesterol level and PPARD rs2016520 in senior individuals aged >/= 65 years. The meta-analysis revealed no association between PPARD rs2016520 and CHD, suggesting ethnic differences in the association between the PPARD locus and CHD.
AIMS: Polymorphism of rs2016520 in gene PPARD has been associated with lipid metabolism, obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). We aimed to study the association of rs2016520 with common metabolic traits in a large population of Han Chi
nese adults. METHODS: The polymorphism was genotyped in 1409 subjects using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS); all participants underwent standard clinical examination and a 75g oral glucose tolerance test (OGTT); associations between the polymorphism and metabolic traits and indices of insulin resistance and insulin sensitivity were analyzed. RESULTS: There was no significant difference in genotypes between the normal glucose tolerance (NGT) and the prediabetes group (chi(2)=3.17, P=0.2), except a nominal difference of allele frequency (chi(2)=3.07, P=0.07). The G carrier presented lower fasting plasma glucose (FPG, P=0.03), lower 2h plasma glucose (Pdom=0.04) and lower fasting insulin (P=0.02), lower systolic blood pressure (SBP, P=0.03), lower HOMA-IR (P=0.02) and higher QUICKI (P=0.01). Moreover, rs2016520 polymorphism was associated with FPG (beta=-0.09, P=0.05), it was also associated with indices of insulin resistance (HOMA-IR, beta=-0.06, Pdom=0.02; fasting insulin, beta=-0.04, P=0.02) and indices of insulin sensitivity (QUICKI, beta=-0.01, P=0.004). In addition, we observed that the allele G was also associated with lower SBP (beta=-1.29, P=0.04) and diastolic blood pressure (DBP, beta=-0.09, P=0.01). However, the minor allele G was not associated with risk of metabolic disorders including prediabetes, overweight, hypertension and metabolic syndrome. CONCLUSIONS: Polymorphism of rs2016520 in gene PPARD was associated with benign metabolic traits in a large cohort of Chinese adults. The G allele may confer protection from type 2 diabetes and hypertension in Han Chinese.
Maternal diabetes significantly increases the risk of congenital malformations, and the mechanisms involved are not yet clarified. This study was designed to address peroxisome proliferator-activated receptor delta (PPARdelta) involvement in diabetic embryopathy. We investigated the concentrations o
f PPARdelta and its endogenous agonist prostaglandin (PG)I(2), as well as the effect of PPARdelta activation on lipid metabolism and PGE(2) concentrations in embryos from control and streptozotocin-induced diabetic rats during early organogenesis. Embryos from diabetic rats showed decreased concentrations of PPARdelta and its endogenous agonist PGI(2) when compared with controls. In embryos from control rats, the addition of the PPARdelta activators (cPGI(2) and PGA(1)) increased embryonic phospholipid levels and de novo phospholipid synthesis studied using (14)C-acetate as a tracer. PGE(2) formed from arachidonate released from phospholipid stores was also up-regulated by PPARdelta activators. In embryos from diabetic rats, reduced phospholipid synthesis and PGE(2) content were observed, and clearly up-regulated by cPGI(2) additions to values similar to those found in control embryos. These data suggest that PPARdelta may play an important role in lipid metabolic and signalling pathways during embryo organogenesis, developmental pathways that are altered in embryos from diabetic rats, possibly as a result of a reduction in levels of PPARdelta and its endogenous activator PGI(2).
Peroxisome proliferator-activated receptor (PPAR)-delta regulates fatty acid oxidation and improves insulin sensitivity. We screened six single nucleotide polymorphisms (SNPs) of the PPAR-delta gene (PPARD) for an association with the conversion from impaired gl
ucose tolerance (IGT) to type 2 diabetes in 769 subjects participating in the STOP-NIDDM trial. A 2.7-fold increase in the risk of diabetes was observed in female carriers of the C allele of rs6902123 (95% CI 1.44-5.30; adjusted P = 0.002). In the placebo group, subjects possessing both the 482Ser allele of the PPAR-gamma coactivator-1alpha gene (PGC-1A) and the rare allele of two SNPs of PPARD (rs6902123 and rs3734254) had up to 2.5-fold increased risk for diabetes. Furthermore, women carrying the C allele of rs6902123 of PPARD and the Pro12Pro genotype of the PPAR-gamma2 gene (PPARG2) had a 3.9-fold (95% CI 1.79-8.63; P = 0.001)-higher risk for diabetes than women with protective genotypes. Expression levels of PPAR-delta in subcutaneous adipose tissue of 87 offspring of Finnish patients with type 2 diabetes did not differ among the genotype groups of SNPs of PPARD. We conclude that SNPs in PPARD modify the conversion from IGT to type 2 diabetes, particularly in combination with the SNPs of PGC-1A and PPARG2.
Li JE, etal., Am J Chin Med. 2015;43(5):879-92. doi: 10.1142/S0192415X15500512. Epub 2015 Jul 30.
Cinnamon is a traditional folk herb used in Asia and has been reported to have antidiabetic effects. Our previous study showed that cinnamaldehyde (CA), a major effective compound in cinnamon, exhibited hypoglycemic and hypolipidemic effects together in db/db mice. The aim of the present study was
to elucidate the molecular mechanisms of the effects of CA on the transcriptional activities of three peroxisome proliferator-activated receptors, (PPAR) alpha, delta, and gamma. We studied the effects of CA through a transient expression assay with TSA201 cells, derivatives of human embryonic kidney cell line (HEK293). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was also performed to evaluate mRNA expression levels. We show here that CA induced PPARdelta, PPARgamma and retinoid X receptor (RXR) activation. CA may activate PPARgamma in a different manner than pioglitazone, as CA selectively stimulated PPARgamma S342A mutant while pioglitazone did not. In addition, CA and L-165041 had a synergistic effect on PPARdelta activation. To gather the biological evidence that CA increases PPARs transcription, we further measured the expressions of PPARdelta and PPARgamma target genes in 3T3-L1 adipocytes. The data showed CA induced the expression of PPARdelta and PPARgamma target genes, namely aP2 and CD36, in differentiated adipocytes. As a result, PPARdelta, PPARgamma and their heterodimeric partner RXR appear to play a part in the CA action in the target tissues, thereby enhancing insulin sensitivity and fatty acid beta-oxidation and energy uncoupling in skeletal muscle and adipose tissue.
The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Several reports have shown that PPARdelta is involved in lipid metabolism, increasing fat oxidation and depleting lipid accumulation. Whether PPARdelta is involved in the
regulation of glucose metabolism is not completely understood. In this study, we examined effects of long-term PPARdelta activation on glycemic control, islet function and insulin sensitivity in diabetic db/db mice. Male db/db mice were administered orally once daily with a selective and partial PPARdelta agonist (NNC 61-5920, 30mg/kg) for eight weeks; control mice received vehicle. Fasting and non-fasting plasma glucose were reduced, reflected in reduced hemoglobinA(1c) (3.6+/-1.6% vs. 5.4+/-1.8 in db/db controls, P<0.05) and furthermore, the AUC(glucose) after oral glucose (3g/kg) was reduced by 67% (P<0.05) after long-term PPARdelta activation. Following intravenous glucose (1g/kg), glucose tolerance was improved after PPARdelta activation (K(G) 1.3+/-0.6 vs. -0.05+/-0.7 %/min, P=0.048). Insulin sensitivity, measured as the glucose clearance after intravenous injection of glucose (1g/kg) and insulin (0.75 or 1.0U/kg), during inhibition of endogenous insulin secretion by diazoxide (25mg/kg), was improved (K(G) 2.9+/-0.6 vs. 1.3+/-0.3 %/min in controls, P<0.05) despite lower insulin levels. Furthermore, islets isolated from PPARdelta agonist treated mice demonstrated improved glucose responsiveness as well as improved cellular topography. In conclusion, PPARdelta agonism alleviates insulin resistance and improves islet function and topography, resulting in improved glycemia in diabetic db/db mice. This suggests that activation of PPARdelta improves glucose metabolism and may therefore potentially be target for treatment of type 2 diabetes.
Shende VR, etal., Biochem J. 2015 Dec 15;472(3):275-86. doi: 10.1042/BJ20150666. Epub 2015 Oct 6.
The hepatic expression of low-density lipoprotein (LDL) receptor (LDLR) gene is regulated primarily at the transcriptional level by a sterol-regulatory element (SRE) in its proximal promoter region which is the site of action of SRE-binding protein 2 (SREBP2). However whether additional cis-regulat
ory elements contribute to LDLR transcription has not been fully explored. We investigated the function of a putative peroxisome proliferator-activated receptor (PPAR)-response element (PPRE) sequence motif located at -768 to -752 bases upstream of the transcription start site of human LDLR gene in response to PPARdelta activation. Promoter luciferase reporter analyses showed that treating HepG2 cells with PPARdelta agonist L165041 markedly increased the activity of a full-length LDLR promoter construct (pLDLR-1192) without any effects on the shorter promoter reporter pLDLR-234 that contains only the core regulatory elements SRE-1 and SP1 sites. Importantly, mutation of the PPRE sequence greatly attenuated the induction of the full-length LDLR promoter activity by L165041 without affecting rosuvastatin (RSV)-mediated transactivation. EMSA and ChIP assay further confirmed the binding of PPARdelta to the LDLR-PPRE site. Treating HepG2 cells with L165041 elevated the mRNA and protein expressions of LDLR without affecting the LDLR mRNA decay rate. The induction of LDLR expression by PPARdelta agonist was further observed in liver tissue of mice and hamsters treated with L165041. Altogether, our studies identify a novel PPRE-mediated regulatory mechanism for LDLR transcription and suggest that combined treatment of statin with PPARdelta agonists may have advantageous effects on LDLR expression.
Tong Y, etal., J Neurol Sci. 2015 Nov 15;358(1-2):82-6. doi: 10.1016/j.jns.2015.08.025. Epub 2015 Aug 17.
PPARdelta belongs to a receptor family of ligand-activated transcription factors involved in the regulation of inflammation, cellular glucose uptake, protection against atherosclerosis and endothelial cell function. Through these effects, they might be involved with the ischemic stroke (IS). We rec
ruited 200 subjects (100 IS patients diagnosed by CTs or/and magnetic resonance imaging (MRI) and 100 normal healthy controls from Chinese Uyghur population) to assess the nature of the functional polymorphisms of PPARdelta +294T/C and any links with IS in this unique population. We found that the C allele of the PPARdelta +294T/C polymorphism was more common in controls than IS subjects in the Uyghur population. C allele carriage may be associated with an increased risk of IS in Uyghurs with a strong trend (OR 1.79, 95% CI: 1.11-2.89). Additionally, the PPARdelta CC and TC genotypes were less frequent in Uyghur population than in Han population. Our population and ethnic-based study demonstrates that the PPARdelta +294C allele maybe an independent risk of IS in Chinese Uyghurs especially in the male (OR 1.99, 95%CI:1.06-3.72) and obesity populations (OR 2.36, 95%CI: 1.19-4.67), which were consistent with Tunisian Population. Moreover, total cholesterol, fasting blood glucose, waist-to-hip ratio, hypertension, history of heart diseases, and negative events may increase the risk of IS, with a trend for HDL to be a protective factor for IS in the Uyghur population. However, larger populations are warranted to validate our findings.
AIMS/HYPOTHESIS: We explored the effects of beta-aminoisobutyric acid (BAIBA) on hyperlipidaemic-condition-induced insulin resistance and inflammation as mediated through a signalling pathway involving AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor delta (PPARdel
ta). METHODS: Mouse skeletal muscle C2C12 cells and C57BL/6J mice were treated with palmitate or a high-fat diet (HFD) and BAIBA. Inflammation and the expression of genes associated with insulin signalling were determined by western blot and quantitative real-time PCR. Selected genes from candidate pathways were evaluated by small interfering (si)RNA knockdown and specific inhibitors. RESULTS: BAIBA treatment ameliorated impairment of insulin receptor substrate (IRS)-1/Akt-mediated insulin signalling in palmitate-treated C2C12 myocytes and in skeletal muscle of HFD-fed mice. In addition, BAIBA treatment reversed HFD-induced increases in body weight and improved impaired glucose tolerance in mice. In vitro and in vivo, inhibitory kappaBalpha (IkappaBalpha) phosphorylation, nuclear factor kappaB (NFkappaB) nuclear translocation and downstream inflammatory cytokines were significantly suppressed by BAIBA. Furthermore, BAIBA treatment significantly induced AMPK phosphorylation and expression of PPARdelta in C2C12 myocytes and in skeletal muscle of mice. Both compound C, an AMPK inhibitor, and Ppardelta (also known as Ppard) siRNA abrogated the inhibitory effects of BAIBA on palmitate-induced inflammation and insulin resistance. BAIBA significantly induced the expression of genes associated with fatty acid oxidation, such as carnitine palmitoyltransferase 1 (Cpt1), acyl-CoA oxidase (Aco; also known as Acox1) and fatty acid binding protein 3 (Fabp3); this effect of BAIBA was significantly reduced by compound C and Ppardelta siRNA. CONCLUSIONS/INTERPRETATION: These results are the first to demonstrate that BAIBA attenuates insulin resistance, suppresses inflammation and induces fatty acid oxidation via the AMPK-PPARdelta pathway in skeletal muscle.
Kurtz M, etal., Life Sci. 2010 May 22;86(21-22):781-90. Epub 2010 Mar 22.
AIMS: Maternal diabetes impairs placental development and metabolism. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors relevant in metabolic homeostasis. We investigated the concentrations of PPARdelta and its endogenous agonist prostacyclin (PGI(2)), as wel
l as the effects of carbaprostacylin (cPGI(2,) a PPARdelta agonist) on lipid metabolism in placentas from control and streptozotocin-induced diabetic rats on day 13.5 of gestation. MAIN METHODS: The placentas were explanted to evaluate PPARdelta expression and PGI(2) concentrations, and cultured with cPGI(2) for further analysis of lipid metabolism (concentrations and (14)C-acetate derived synthesis of triglycerides, cholesteryl esters, phospholipids, cholesterol and free fatty acids; release of glycerol and lipid peroxidation). KEY FINDINGS: Reduced PGI(2) concentrations were found in the placentas from diabetic rats when compared to controls. cPGI(2) additions reduced the concentrations and synthesis of several lipid species, increased lipid catabolism and reduced lipid peroxidation in the placenta. These effects were more marked in diabetic tissues, which presented alterations in the lipid metabolic parameters evaluated. cPGI(2) additions increased placental PPARdelta and acyl-CoA oxidase expression, which are changes possibly involved in the catabolic effects observed. SIGNIFICANCE: The present study reveals the capability of cPGI(2) to regulate placental lipid metabolism and PPARdelta expression, and suggests that preserving appropriate PGI(2) concentrations in the placenta may help to metabolize maternal derived lipid overload in diabetic gestations.
Ji MJ, etal., Int J Neuropsychopharmacol. 2015 Sep 10;19(1). pii: pyv083. doi: 10.1093/ijnp/pyv083.
BACKGROUND: Emerging data have demonstrated that peroxisome proliferator-activated receptor delta (PPARdelta) activation confers a potentially neuroprotective role in some neurodegenerative diseases. However, whether PPARdelta is involved in depression is unknown. METHODS: In this study, PPARdelta w
as firstly investigated in the chronic mild stress (CMS) and learned helplessness (LH) models of depression. The changes in depressive behaviors and hippocampal neurogenesis were investigated after PPARdelta overexpression by microinfusion of the lentiviral vector, containing the coding sequence of mouse PPARdelta (LV-PPARdelta), into the bilateral dentate gyri of the hippocampus or PPARdelta activation by repeated systemic administration of PPARdelta agonist GW0742 (5 or 10mg/kg.d, i.p., for 21 d). RESULTS: We found that both CMS and LH resulted in a significant decrease in the PPARdelta expression in the hippocampi of mice, and this change was reversed by treatment with the antidepressant fluoxetine. PPARdelta overexpression and PPARdelta activation each suppressed the CMS- and LH-induced depressive-like behavior and produced an antidepressive effect. In vivo or in vitro studies also showed that both overexpression and activation of PPARdelta enhanced proliferation or differentiation of neural stem cells in the hippocampi of mice. CONCLUSIONS: These results suggest that hippocampal PPARdelta upregulation represses stress-induced depressive behaviors, accompanied by enhancement of neurogenesis.
Pesant M, etal., Cardiovasc Res. 2006 Feb 1;69(2):440-9. Epub 2005 Dec 6.
OBJECTIVE: Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma plays beneficial roles in cardiovascular disorders such as atherosclerosis and heart reperfusion. Although PPARalpha and gamma have been documented to reduce oxidative stress in the vasculature and th
e heart, the role of PPARdelta remains poorly studied. METHODS AND RESULTS: We focused on PPARdelta function in the regulation of oxidative stress-induced apoptosis in the rat cardiomyoblast cell line H9c2. Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we showed that PPARdelta is the predominantly expressed isotype whereas PPARalpha was weakly detected. By performing cell viability assays, we also showed that the selective PPARdelta agonist GW501516 protected cells from H(2)O(2)-induced cell death. The protective effect of GW501516 was due to an inhibition of H(2)O(2)-triggered apoptosis as shown by annexin-V labeling, DNA fragmentation analysis, and caspase-3 activity measurement. We demonstrated by transient transfection of a dominant negative mutant of PPARdelta that the protection induced by GW501516 was totally dependent on PPARdelta. Semi-quantitative RT-PCR and Western blotting analysis demonstrated that GW501516 treatment upregulated catalase. Moreover, forced overexpression of catalase inhibited H(2)O(2)-triggered apoptosis, as evidenced by annexin-V labeling. CONCLUSION: Taken together, our results account for an important role of PPARdelta in inhibiting the onset of oxidative stress-induced apoptosis in H9c2 cells. PPARdelta appears to be a new therapeutic target for the regulation of heart reperfusion-associated oxidative stress and stimulation of enzymatic antioxidative defences.
The goal of epidermal ontogenesis is to form a stratum corneum (SC), which is required for post-natal permeability barrier function. The regulation of epidermal ontogenesis is poorly understood, but nuclear hormone receptors have been shown to have an important function. As peroxisome proliferator-a
ctivated receptor-delta (PPARdelta) is very abundant in fetal epidermis and PPARdelta activation stimulates differentiation and permeability barrier formation in adults, we hypothesized that PPARdelta might regulate epidermal ontogenesis. Treatment of fetal rat explants with the PPARdelta ligand, GW 610742X, accelerates permeability barrier development, evidenced by a decrease in transepidermal water loss and an enhanced outside-in barrier function, attributable to the presence of more mature lamellar membranes in the SC and enhanced expression of loricrin and involucrin. Similarly, the intra-amniotic administration of GW 610742X also accelerates the formation of the SC and permeability barrier development. Finally, in PPARdelta-deficient mice the formation of the SC and the expression of differentiation-related proteins were delayed on days 16.5 and 17.5 of gestation. However, at later stages (day 18.5 and after birth), there were no differences between wild-type- and PPARdelta-deficient mice, indicating only a transient delay in epidermal ontogenesis. These studies show that PPARdelta has a role in SC formation and permeability barrier development.
The peroxisome proliferator-activated receptor delta (PPARdelta) is implicated in regulation of mitochondrial processes in a number of tissues, and PPARdelta activation is associated with decreased susceptibility to ectopic lipid deposition and metabolic disease. Here, we show that PPARdelta is the
PPAR subtype expressed at the highest level in insulinoma cells and rat pancreatic islets. Furthermore, PPARdelta displays high transcriptional activity and acts in pronounced synergy with retinoid-X-receptor (RXR). Interestingly, unsaturated fatty acids mimic the effects of synthetic PPARdelta agonists. Using short hairpin RNA-mediated knockdown, we demonstrate that the ability of unsaturated fatty acids to stimulate fatty acid metabolism is dependent on PPARdelta. Activation of PPARdelta increases the fatty acid oxidation capacity in INS-1E beta-cells, enhances glucose-stimulated insulin secretion (GSIS) from islets, and protects GSIS against adverse effects of prolonged fatty acid exposure. The presented results indicate that the nuclear receptor PPARdelta is a fatty acid sensor that adapts beta-cell mitochondrial function to long-term changes in unsaturated fatty acid levels. As maintenance of mitochondrial metabolism is essential to preserve beta-cell function, these data indicate that dietary or pharmacological activation of PPARdelta and RXR may be beneficial in the prevention of beta-cell dysfunction.
Hwang JS, etal., Int J Biochem Cell Biol. 2015 May;62:54-61. doi: 10.1016/j.biocel.2015.02.014. Epub 2015 Feb 27.
The peroxisome proliferator-activated receptor delta (PPARdelta) has been implicated in the modulation of vascular homeostasis. However, its roles in the apoptotic cell death of vascular smooth muscle cells (VSMCs) are poorly understood. Here, we demonstrate that PPARdelta modulates oxidized low-den
sity lipoprotein (oxLDL)-induced apoptosis of VSMCs through the transforming growth factor-beta (TGF-beta) and focal adhesion kinase (FAK) signaling pathways. Activation of PPARdelta by GW501516, which is a specific ligand, significantly inhibited oxLDL-induced cell death and generation of reactive oxygen species in VSMCs. These inhibitory effects were significantly reversed in the presence of small interfering (si)RNA against PPARdelta, or by blockade of the TGF-beta or FAK signaling pathways. Furthermore, PPARdelta-mediated recovery of FAK phosphorylation suppressed by oxLDL was reversed by SB431542, a specific ALK5 receptor inhibitor, indicating that a TGF-beta/FAK signaling axis is involved in the action of PPARdelta. Among the protein kinases activated by oxLDL, p38 mitogen-activated protein kinase was suppressed by ligand-activated PPARdelta. In addition, oxLDL-induced expression and translocation of pro-apoptotic or anti-apoptotic factors were markedly affected in the presence of GW501516. Those effects were reversed by PPARdelta siRNA, or inhibitors of TGF-beta or FAK, which also suggests that PPARdelta exerts its anti-apoptotic effect via a TGF-beta/FAK signaling axis. Taken together, these findings indicate that PPARdelta plays an important role in the pathophysiology of disease associated with apoptosis of VSMC, such as atherosclerosis and restanosis.
Kim JA, etal., Muscle Nerve. 2016 Feb;53(2):287-96. doi: 10.1002/mus.24723. Epub 2015 Nov 26.
INTRODUCTION: Skeletal muscle oxidative capacity decreases and fatigability increases after spinal cord injury. Transcription factor peroxisome proliferator-activated receptor delta (PPARdelta) promotes a more oxidative phenotype. METHODS: We asked whether PPARdelta overexpression could ameliorate t
hese deficits in the medial gastrocnemius of spinal cord transected (ST) adult mice. RESULTS: Time-to-peak tension and half-relaxation times were longer in PPARdelta-Con and PPARdelta-ST compared with littermate wild-type (WT) controls. Fatigue index was 50% higher in PPARdelta-Con than WT-Con and 70% higher in the PPARdelta-ST than WT-ST. There was an overall higher percent of darkly stained fibers for succinate dehydrogenase in both PPARdelta groups. CONCLUSIONS: The results indicate a conversion toward slower, more oxidative, and less fatigable muscle properties with overexpression of PPARdelta. Importantly, the elevated fatigue resistance was maintained after ST, suggesting that enhanced PPARdelta expression, and possibly small molecule agonists, could ameliorate the increased fatigability routinely observed in chronically paralyzed muscles.
Ingestion of a high-fat diet composed mainly of the saturated fatty acid, palmitic (PA), and the unsaturated fatty acid, oleic (OA), stimulates transcription in the brain of the opioid neuropeptide, enkephalin (ENK), which promotes intake of substances of abuse. To understand possible underlying mec
hanisms, this study examined the nuclear receptors, peroxisome proliferator-activated receptors (PPARs), and tested in hypothalamic and forebrain neurons from rat embryos whether PPARs regulate endogenous ENK and the fatty acids themselves affect these PPARs and ENK. The first set of experiments demonstrated that knocking down PPARdelta, but not PPARalpha or PPARgamma, increased ENK transcription, activation of PPARdelta by an agonist decreased ENK levels, and PPARdelta neurons coexpressed ENK, suggesting that PPARdelta negatively regulates ENK. In the second set of experiments, PA treatment of hypothalamic and forebrain neurons had no effect on PPARdelta protein while stimulating ENK mRNA and protein, whereas OA increased both mRNA and protein levels of PPARdelta in forebrain neurons while having no effect on ENK mRNA and increasing ENK levels. These findings show that PA has a strong, stimulatory effect on ENK and weak effect on PPARdelta protein, whereas OA has a strong stimulatory effect on PPARdelta and weak effect on ENK, consistent with the inhibitory effect of PPARdelta on ENK. They suggest a function for PPARdelta, perhaps protective in nature, in embryonic neurons exposed to fatty acids from a fat-rich diet and provide evidence for a mechanism contributing to differential effects of saturated and monounsaturated fatty acids on neurochemical systems involved in consummatory behavior. Our findings show that PPARdelta in forebrain and hypothalamic neurons negatively regulates enkephalin (ENK), a peptide known to promote ingestive behavior. This inverse relationship is consistent with our additional findings, that a saturated (palmitic; PA) compared to a monounsaturated fatty acid (oleic; OA) has a strong stimulatory effect on ENK and weak effect on PPARdelta. These results suggest that PPARdelta protects against the neuronal effects of fatty acids, which differentially affect neurochemical systems involved in ingestive behavior.
Zhao Y, etal., Cell Metab. 2016 Apr 12;23(4):699-711. doi: 10.1016/j.cmet.2016.02.019. Epub 2016 Mar 24.
High sodium intake is a major risk factor for developing hypertension in diabetes. Promotion of sodium excretion reduces cardiometabolic lesions in diabetes. However, the interaction between sodium intake and glucose homeostasis remains elusive. Here, we report that high sodium intake remarkably in
creased natriuresis in wild-type mice, but this effect was blunted in adipose-specific PPARdelta knockout mice and diabetic mice. PPARdelta activation in perirenal fat by agonist or high sodium intake inhibited renal sodium-glucose cotransporter 2 (SGLT2) function, which is mediated by increased production of adipose adiponectin. In addition, high salt intake-induced natriuresis was impaired in diabetic states because of renal SGLT2 dysfunction. Type 2 diabetic patients with uncontrolled hyperglycemia had less natriuresis that was correlated to their plasma adiponectin levels. Our findings provide insights into the distinctive role of the PPARdelta/adiponectin/SGLT2 pathway in the regulation of sodium and glucose homeostasis.
Peroxisome proliferator-activated receptor delta (PPARdelta) is a critical regulator of energy metabolism in the heart. Here, we propose a mechanism that integrates two deleterious characteristics of heart failure, hypoxia and a metabolic shift toward glycolysis, involving the microRNA cluster miR-1
99a approximately 214 and PPARdelta. We demonstrate that under hemodynamic stress, cardiac hypoxia activates DNM3os, a noncoding transcript that harbors the microRNA cluster miR-199a approximately 214, which shares PPARdelta as common target. To address the significance of miR-199a approximately 214 induction and concomitant PPARdelta repression, we performed antagomir-based silencing of both microRNAs and subjected mice to biomechanical stress to induce heart failure. Remarkably, antagomir-treated animals displayed improved cardiac function and restored mitochondrial fatty acid oxidation. Taken together, our data suggest a mechanism whereby miR-199a approximately 214 actively represses cardiac PPARdelta expression, facilitating a metabolic shift from predominant reliance on fatty acid utilization in the healthy myocardium toward increased reliance on glucose metabolism at the onset of heart failure.
Kino T, etal., Eur J Clin Invest. 2007 May;37(5):425-33.
BACKGROUND: Interleukin-6 and downstream liver effectors acute phase reactants are implicated in the systemic inflammatory reaction. Peroxisome proliferator-activated receptor delta (PPARdelta), which binds to and is activated by a variety of fatty acids, was recently shown to have anti-inflammatory
actions. MATERIALS AND METHODS: We examined the ability of the synthetic PPARdelta agonist GW501516 to suppress interleukin-6-induced expression of acute phase proteins in human hepatoma HepG2 cells and rat primary hepatocytes. Results GW501516 dose-dependently suppressed interleukin-6-induced mRNA expression of the acute phase protein alpha1-antichymotrypsin in HepG2 cells. The compound also suppressed interleukin-6-induced mRNA expression of alpha2-acid glycoprotein, beta-fibrinogen and alpha2-macroglobulin in and the secretion of C-reactive protein by rat primary hepatocytes. Depletion of the PPARdelta receptor, but not of PPARalpha or gamma, attenuated the suppressive effect of GW501516 on interleukin-6-induced alpha1-antichymotrypsin mRNA expression, indicating that PPARdelta specifically mediated this effect. Since interleukin-6 stimulates the transcriptional activity of the alpha1-antichymotrypsin promoter by activating the signal transducer and activator of transcription (STAT) 3, we examined functional interaction of this transcription factor and PPARdelta on this promoter. Overexpression of PPARdelta enhanced the suppressive effect of GW501516 on STAT3-activated transcriptional activity of the alpha1-antichymotrypsin promoter, while GW501516 suppressed interleukin-6-induced binding of this transcription factor to this promoter. CONCLUSIONS: These findings indicate that agonist-activated PPARdelta interferes with interleukin-6-induced acute phase reaction in the liver by inhibiting the transcriptional activity of STAT3. PPARdelta agonists might be useful for the suppression of systemic inflammatory reactions in which IL-6 plays a central role.
Dimopoulos N, etal., FEBS Lett. 2007 Oct 2;581(24):4743-8. Epub 2007 Sep 6.
Peroxisome proliferator-activated receptor-delta (PPARdelta) activation enhances skeletal muscle fatty acid oxidation and improves whole body glucose homeostasis and insulin sensitivity. Recently, GW501516, a selective PPARdelta agonist, was reported to increase glucose uptake in human skeletal my
otubes by an AMPK-dependent mechanism that may contribute to the improved glucose tolerance. Here, we demonstrate that whilst GW501516 increases expression of PGC-1alpha and CPT-1 and stimulates fatty-acid oxidation in L6 myotubes, it fails to enhance insulin sensitivity, AMPK activity or glucose uptake and storage. Our findings exclude sarcolemmal glucose transport as a potential target for the therapeutic action of PPARdelta agonists in skeletal muscle.
The mechanisms of WNT/beta-catenin signaling involved in airway inflammation of chronic obstructive pulmonary disease (COPD) remain unknown, although recent observations have suggested an important contribution of the pathway in pulmonary parenchymal tissue repair and airway epithelium differentiati
on. We investigated the role of WNT/beta-catenin signaling in cigarette smoke (CS)-related airway inflammation using patient lung tissues, human bronchial epithelial cells (16HBECs), and mouse models. Reduced activity of WNT/beta-catenin signaling was observed in the airway epithelium of smokers with or without COPD. The mRNA expression of WNT transcription factor TCF4 negatively correlated with the pack year. The mRNA levels of WNT receptor FZD4 negatively correlated with the mRNA levels of IL-1beta. CS exposure decreased the activity of WNT/beta-catenin signaling in both 16HBECs and mice. In vitro studies demonstrated the upregulation of inflammatory cytokines TNF-alpha and IL-1beta secretion induced by CS extract (CSE) could be attenuated by beta-catenin activator SB216763 and be exacerbated by beta-catenin small-interfering RNA (siRNA), respectively. Furthermore, the decrease in the expression of peroxisome proliferator-activated receptor (PPARdelta) induced by CSE stimulation could be rescued by SB216763. SB216763 also attenuated the upregulation of phosphorylated p38 mitogen-activated protein kinase (MAPK) stimulated by CSE. Both PPARdelta agonist and p38 MAPK inhibitor could suppress the TNF-alpha and IL-1beta release induced by CSE treatment. In addition, PPARdelta activation could abolish beta-catenin siRNA-mediated aggravation of phosphorylated p38 MAPK in response to CSE. Finally, SB216763 treatment significantly ameliorated peribronchial inflammatory cell infiltration, leukocyte influx, and the release of TNF-alpha and IL-1beta in the bronchoalveolar lavage fluid of CS-exposed mice. Taken together, our findings indicate that the reduced activity of WNT/beta-catenin signaling induced by CS may promote inflammatory cytokine production in airway epithelium and have an essential role in airway inflammation in COPD by PPARdelta/p38 MAPK pathway.
