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At least 19 recordsLinked to original sources
PubMed2005

Regulatory role of peroxisome proliferator-activated receptor delta (PPAR delta) in muscle metabolism. A new target for metabolic syndrome treatment?

Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in both developmental and metabolic functions. There are activated by fatty acids, fatty acid metabolites, and synthetic compounds marketed for their lipid-lowering and antidiabetic actions. It was clearly established that activation of PPAR alpha and PPAR gamma, by fibrates and thiazolidinediones, respectively, impair metabolic disorders. The implication of the third member of the PPAR family, PPAR delta, remained evasive until recently. These past few years, it has been demonstrated that treatment with PPAR delta agonists normalizes blood lipids, reduces insulin resistance and adiposity in rodent and primate. Utilization of both cellular and animal models revealed that the nuclear receptor plays a central role in the control of fatty acid burning in adipose tissue and skeletal muscle. Furthermore, PPAR delta appeared to be important for adaptive response of skeletal muscle to environmental changes, such as physical exercise.

Animals↗
PubMed2001

Prostacyclin-dependent apoptosis mediated by PPAR delta.

Prostacyclin (PGI(2)) plays important roles in hemostasis both as a vasodilator and an endogenous inhibitor of platelet aggregation. PGI(2) functions in these roles through a specific IP receptor, a G protein-coupled receptor linked to G(s) and increases in cAMP. Here, we report that intracellular prostacyclin formed by expressing prostacyclin synthase in human embryonic kidney 293 cells promotes apoptosis by activating endogenous peroxisome proliferator-activated receptor delta (PPAR delta). In contrast, treatment of cells with extracellular prostacyclin or dibutyryl cAMP actually reduced apoptosis. On the contrary, treatment of the cells with RpcAMP (adenosine 3',5'-cyclic monophosphothioate, Rp-isomer), an antagonist of cAMP, enhanced prostacyclin-mediated apoptosis. The expression of an L431A/G434A mutant of PPAR delta completely blocked prostacyclin-mediated PPAR delta activation and apoptosis. These observations indicate that prostacyclin can act through endogenous PPAR delta as a second signaling pathway that controls cell fate.

Amino Acid Sequence↗
PubMed1995

Rat PPAR delta contains a CGG triplet repeat and is prominently expressed in the thalamic nuclei.

We have isolated a new rat sequence containing motifs of a nuclear hormone receptor from a brain cDNA library. The deduced amino acid sequence encoded by the cDNA clone showed a strong homology to the human NUCI and the mouse peroxisome proliferator activated receptor delta (PPAR delta). We therefore refer to this new clone as rat PPAR delta (rPPAR delta). The new feature of rPPAR delta is a 14 CGG triplet repeat on the 5' untranslated region, not previously reported in either NUCI or mPPAR delta. We found that rPPAR delta was expressed as a 3.5-kb transcript which showed a wide distribution in adult rat tissues. Abundant expression was detected in brain, heart, skeletal muscle, kidney and lung. Weaker expression was noted in the liver, spleen and testis. To determine the specific brain localization of rPPAR delta we performed in situ hybridization analysis. Prominent expression was observed in the thalamus, particularly in the posterior part of the ventral medial nucleus, a site responsive to pain and cold stress. These results raise the possibility that PPAR delta might play a role in modulating response to thermal and pain sensations.

Amino Acid Sequence↗
PubMed2006

Activation of PPAR-delta in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids.

AIMS/HYPOTHESIS: GW501516, an agonist of peroxisome proliferator-activated receptor-delta (PPAR-delta), increases lipid combustion and exerts antidiabetic action in animals, effects which are attributed mainly to direct effects on skeletal muscle. We explored such actions further in isolated rat skeletal muscle. MATERIALS AND METHODS: Specimens of rat skeletal muscle were pretreated with GW501516 (0.01-30 mumol/l) for 0.5, 4 or 24 h and rates of fuel metabolism were then measured. In addition, effects on mitochondrial function were determined in isolated rat liver mitochondria. RESULTS: At concentrations between 0.01 and 1 mumol/l, GW501516 dose-dependently increased fatty acid oxidation but reduced glucose utilisation in isolated muscle. Thus after 24 h of preincubation with 1 mumol/l GW501516, palmitate oxidation increased by +46+/-10%, and the following decreased as specified: glucose oxidation -46+/-8%, glycogen synthesis -42+/-6%, lactate release -20+/-2%, glucose transport -15+/-6% (all p<0.05). Reduction of glucose utilisation persisted independently of insulin stimulation or muscle fibre type, but depended on fatty acid availability (the effect on glucose transport in the absence of fatty acids was an increase of 30+/-9%, p<0.01), suggesting a role for the glucose-fatty acid cycle. At higher concentrations, GW501516 uncoupled oxidative phosphorylation by direct action on isolated mitochondria. CONCLUSIONS/INTERPRETATION: GW501516-induced activation of PPAR-delta reduces glucose utilisation by skeletal muscle through a switch in mitochondrial substrate preference from carbohydrate to lipid. High concentrations of GW501516 induce mitochondrial uncoupling independently of PPAR-delta.

AMP-Activated Protein Kinases↗
PubMed2006

BCL-6: a possible missing link for anti-inflammatory PPAR-delta signalling in pancreatic beta cells.

AIMS/HYPOTHESIS: Inflammatory mediators contribute to pancreatic beta cell death in type 1 diabetes. Beta cells respond to cytokine exposure by activating gene networks that alter cellular metabolism, induce chemokine release (thereby increasing insulitis), and cause apoptosis. We have previously shown by microarray analysis that exposure of INS-1E cells to IL-1beta + IFN-gamma induces the transcription factor peroxisome proliferator-activated receptor (Ppar)-delta and several of its target genes. PPAR-delta controls cellular lipid metabolism and is a major regulator of inflammatory responses. We therefore examined the role of PPAR-delta in cytokine-treated beta cells. MATERIALS AND METHODS: Primary beta cells that had been purified by fluorescence-activated cell sorting and INS-1E cells were cultured in the presence of the cytokines TNF-alpha, IL-1beta, or IL-1beta + IFN-gamma, or the synthetic PPAR-delta agonist GW501516. Gene expression was analysed by real-time PCR. PPAR-delta, monocyte chemoattractant protein (MCP-1, now known as CCL2) promoter and NF-kappaB activity were determined by luciferase reporter assays. RESULTS: Exposure of primary beta cells or INS-1E cells to cytokines induced Ppar-delta mRNA expression and PPAR-delta-dependent CD36, lipoprotein lipase, acyl CoA synthetase and adipophilin mRNAs. Cytokines and the PPAR-delta agonist GW501516 also activated a PPAR-delta response element reporter in beta cells. Unlike immune cells, neither INS-1E nor beta cells expressed the transcriptional repressor B-cell lymphoma-6 (BCL-6). As a consequence, PPAR-delta activation by GW501516 did not decrease cytokine-induced Mcp-1 promoter activation or mRNA expression, as reported for macrophages. Transient transfection with a BCL-6 expression vector markedly reduced Mcp-1 promoter and NF-kappaB activities in beta cells. CONCLUSIONS/INTERPRETATION: Cytokines activate the PPAR-delta gene network in beta cells. This network does not, however, regulate the pro-inflammatory response to cytokines because beta cells lack constitutive BCL-6 expression. This may render beta cells particularly susceptible to propagating inflammation in type 1 diabetes.

Animals↗
PubMed2003

The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-delta to induce apoptosis in colorectal cancer cells.

Diminished apoptosis, a critical event in tumorigenesis, is linked to down-regulated 15-lipoxygenase-1 (15-LOX-1) expression in colorectal cancer cells. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which is the primary product of 15-LOX-1 metabolism of linoleic acid, restores apoptosis. Nonsteroidal antiinflammatory drugs (NSAIDs) transcriptionally up-regulate 15-LOX-1 expression to induce apoptosis. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for linoleic and arachidonic acid metabolites. PPAR-delta promotes colonic tumorigenesis. NSAIDs suppress PPAR-delta activity in colon cancer cells. The mechanistic relationship between 15-LOX-1 and PPAR-delta was previously unknown. Our current study shows that (i) 13-S-HODE binds to PPAR-delta, decreases PPAR-delta activation, and down-regulates PPAR-delta expression in colorectal cancer cells; (ii) the induction of 15-LOX-1 expression is a critical step in NSAID down-regulation of PPAR-delta and the resultant induction of apoptosis; and (iii) PPAR-delta is an important signaling receptor for 13-S-HODE-induced apoptosis. The in vivo relevance of these mechanistic findings was demonstrated in our tumorigenesis studies in nude mouse xenograft models. Our findings indicate that the down-regulation of PPAR-delta by 15-LOX-1 through 13-S-HODE is an apoptotic signaling pathway that is activated by NSAIDs.

Animals↗
PubMed2002

Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta.

Ablation of peroxisome proliferator activated receptor (PPAR) alpha, a lipid-activated transcription factor that regulates expression of beta-oxidative genes, results in profound metabolic abnormalities in liver and heart. In the present study we used PPAR alpha knockout (KO) mice to determine whether this transcription factor is essential for regulating fuel metabolism in skeletal muscle. When animals were challenged with exhaustive exercise or starvation, KO mice exhibited lower serum levels of glucose, lactate, and ketones and higher nonesterified fatty acids than wild type (WT) littermates. During exercise, KO mice exhausted earlier than WT and exhibited greater rates of glycogen depletion in liver but not skeletal muscle. Fatty acid oxidative capacity was similar between muscles of WT and KO when animals were fed and only 28% lower in KO muscles when animals were starved. Exercise-induced regulation and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, two classical and robustly responsive PPAR alpha target genes, were similar between WT and KO in skeletal muscle but markedly different between genotypes in heart. Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPAR delta is severalfold more abundant than either PPAR alpha or PPAR gamma. In both human and rodent myocytes, the highly selective PPAR delta agonist GW742 increased fatty acid oxidation about 2-fold and induced expression of several lipid regulatory genes, including pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, responses that were similar to those elicited by the PPAR alpha agonist GW647. These results show redundancy in the functions of PPARs alpha and delta as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the delta-subtype can compensate for deficiency of PPAR alpha.

Animals↗
PubMed2003

Evaluation of human peroxisome proliferator-activated receptor (PPAR) subtype selectivity of a variety of anti-inflammatory drugs based on a novel assay for PPAR delta(beta).

The nuclear receptor PPAR (peroxisome proliferator-activated receptor) has three subtypes named alpha, delta(beta), and gamma that may act as receptors for a range of compounds including antihyperglycaemic drugs, insulin sensitizers, and non-steroidal anti-inflammatory drugs (NSAIDs). Although profiling of the subtype selectivity of the compounds for PPAR is indispensable to elucidate their pharmacological action, the absence of an appropriate transactivation assay for PPAR delta led us to develop a sensitive and reproducible method. We found that co-expression of PPAR delta, retinoid X receptor (RXR) alpha, and coactivators such as CBP and SRC-1 enhanced basal and agonist-dependent activation of PPAR responsive element (PPRE)-driven transcription by PPAR delta, rendering a PPRE-driven reporter assay reliable and sensitive. Utilizing this assay for PPAR delta, we re-evaluated the subtype selectivity of a variety of anti-inflammatory drugs for human PPAR. The PPAR agonists tested included two leukotriene (LT) D(4) antagonist, seven NSAIDs, and two anti-rheumatoid drugs. We found that a novel LTD(4) antagonist, FK011 ([2-(((2-(4-tert-butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl)oxy)methyl)phenyl]acetic acid), showed marked agonistic activity for PPAR gamma. NSAIDs were classified into the following three groups: those showing no activity for all subtypes, those that were selective for PPAR gamma such as indomethacin and diclofenac, and those showing agonistic activity for the delta and gamma subtypes such as ibuprofen. These results will be important to studies on the molecular mechanisms of pharmacological actions of LTD(4) antagonists and NSAIDs.

Animals↗
PubMed2001

PPAR delta agonists stimulate oligodendrocyte differentiation in tissue culture.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily that have been described as master genes that switch cells from an undifferentiated phenotype to a differentiated phenotype. In the present investigation, we examined the possibility that ligands for PPARs are potent activators of oligodendrocyte (OL) differentiation and/or proliferation. Primary glial cultures and enriched OL cultures of neonatal mouse cerebra were treated with three different PPAR agonists: a PPAR gamma-selective agonist, a PPAR delta-selective agonist, and a pan agonist selective for both PPAR gamma and delta. Treatment with PPAR gamma agonist does not have an effect on the differentiation of OLs; however, PPAR delta agonist and the pan agonist treatment accelerates the differentiation of OLs within 24 h of application in mixed glial cultures. The number of OLs with processes and huge membrane sheets increases two- to threefold in both groups. The increase in the size of the sheets is also mirrored by changes in the intensity and distribution of myelin basic protein (MBP) and proteolipid protein (PLP) mRNAs. As compared to controls, the PPAR delta agonist-treated groups contain more OLs that have MBP and PLP mRNA extending into distal processes. These results indicate that PPAR delta plays a significant role in the maturation of OLs and regulates the size of OL sheets. BrdU immunostaining reveals that these agonists do not significantly stimulate proliferation of OLs expressing glycolipids. The studies in enriched OL cultures reproduce the effects of the PPAR agonists seen in the mixed glial cultures, indicating that the effect of the PPAR agonists is directly on the OLs and not via astrocytes. In the enriched cultures, the total number of OLs increases significantly in the PPAR delta agonist-treated groups, but BrdU immunostaining does not show an increased proliferation of cells. These findings suggest that PPAR delta increases the survival of cells and/or prevents cell death in enriched cultures. Although PPAR delta is expressed in various cell types, its role as a factor in the transcriptional regulation of OL differentiation has not been explored. We show for the first time that a ligand that serves as an agonist for PPAR delta activates the program of OL differentiation in primary and enriched OL cultures.

Animals↗
PubMedDate not supplied

PPAR delta functions as a prostacyclin receptor in blastocyst implantation.

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone superfamily, are the target of extensive investigation because of their role in various pathophysiological processes. Recently, a novel biological function of PPAR delta, a less studied member of the family, was observed in the mouse. Evidence suggests that cyclooxygenase 2-derived prostacyclin mediates blastocyst implantation via this receptor. In this review, this new function of PPAR delta in implantation is highlighted, and future directions to investigate its mechanism of action are discussed.

Animals↗
PubMedDate not supplied

Human skeletal muscle fibre type variations correlate with PPAR alpha, PPAR delta and PGC-1 alpha mRNA.

AIMS: Studies from genetically modified animals have been instrumental in highlighting genes and their products involved in the regulation of muscle fibre type and oxidative phenotypes; however, evidence in humans is limited. Our aim was therefore to investigate expression of those genes implicated in the regulation of oxidative fibre phenotypes in humans. METHODS: Using quantitative polymerase chain reaction we determined mRNA expression of selected genes in skeletal muscle from three different groups, displaying physiological and pathological variations in muscle fibre type, activity and skeletal muscle metabolism respectively: (i) elite athletes (cyclists), with an increased proportion of type I slow twitch, oxidative fibres, (ii) normally active subjects with an average fibre type distribution, and (iii) spinal cord-injured subjects with a low proportion of type I fibres. RESULTS: Skeletal muscle mRNA expression of calcineurin Aalpha and Abeta, peroxisome proliferator-activated receptor (PPAR)-alpha and -delta, and PPAR gamma coactivator (PGC)-1alpha and -1beta was determined. Calcineurin Aalpha and calcineurin Abeta mRNA expression was similar between groups. In contrast, mRNA expression of PPARalpha, PPARdelta, PGC-1alpha and -1beta was increased in athletes, when compared with normally active subjects. Furthermore, mRNA expression of PPARalpha, PPARdelta, PGC-1alpha and -1beta was reduced in spinal cord-injured subjects. Additionally, PPARalpha, PPARdelta and PGC-1alpha correlated with oxidative fibre content. CONCLUSION: Skeletal muscle mRNA expression of PPARalpha, PPARdelta, PGC-1alpha and -1beta reflects differences in type I muscle fibres associated with pathologically and physiologically induced skeletal muscle fibre type differences.

Adult↗
PubMed2007

PPAR delta agonists and metabolic diseases.

Peroxisome proliferator-activated receptors (PPARs) are the key transcription factors regulating lipid metabolism and energy homeostasis. PPARalpha and PPARgamma are known therapeutic targets for hypertriglyceridemia and type 2 diabetes, respectively. The physiologic function of the third member, PPARdelta, has been difficult to define due to its broad tissue distribution. Through the creation of transgenic mouse models and identification of high-affinity synthetic ligands, the diverse activities of PPARdelta in several metabolically active tissues, including skeletal muscle, adipose tissue, liver, and macrophages, have recently been revealed. These metabolic activities of PPARdelta implicate the potential use of PPARdelta agonists to treat metabolic diseases, including atherosclerosis and insulin resistance.

Animals↗
PubMed2005

PPAR delta: an uncompletely known nuclear receptor.

Peroxisome proliferator-activated receptors (PPAR) mediate some of the transcriptional effects of fatty acids and control many physiological functions, especially in the field of development and metabolism. Three isotypes are known, alpha, gamma, and B/delta. Roles of PPAR alpha and PPARgamma are now quite well-known, particularly since their pharmacologic ligands have been marketed, respectively the lipid-normalizing class of fibrates and the antidiabetic class of thiazolidinediones (glitazones). However, functions of PPARdelta are uncompletely known to date, but some recent data enlight its role in the regulation of fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue. Overexpression of PPARdelta using a transgenic murine model promotes an increase of muscle oxidative capability. This is accompanied by a redistribution of fatty acid flux, redirected from adipose tissue towards skeletal muscle. Finally, adipose mass is reduced, due to a decreased adipocyte size. These data strongly suggest that PPARdelta play a major role in the metabolic adaptations to western diet characterized by an excessive amount of saturated fat. Considering the metabolic properties of the two other PPAR isotypes, alpha and gamma, it is likely that the three PPAR isotypes have complementary effects in the pathophysiology of obesity and metabolic syndrome. Future therapeutical perspectives in this field should consider combined treatment, adding delta agonists (for all that their safety will be established) to the already available alpha and gamma agonists.

Animals↗
PubMed2000

Alteration of a single amino acid in peroxisome proliferator-activated receptor-alpha (PPAR alpha) generates a PPAR delta phenotype.

Three pharmacologically important nuclear receptors, the peroxisome proliferator-activated receptors (PPARs alpha, gamma, and delta), mediate key transcriptional responses involved in lipid homeostasis. The PPAR alpha and gamma subtypes are well conserved from Xenopus to man, but the beta/delta subtypes display substantial species variations in both structure and ligand activation profiles. Characterization of the avian cognates revealed a close relationship between chick (c) alpha and gamma subtypes to their mammalian counterparts, whereas the third chicken subtype was intermediate to Xenopus (x) beta and mammalian delta, establishing that beta and delta are orthologs. Like xPPAR beta, cPPAR beta responded efficiently to hypolipidemic compounds that fail to activate the human counterpart. This provided the opportunity to address the pharmacological problem as to how drug selectivity is achieved and the more global evolutionary question as to the minimal changes needed to generate a new class of receptor. X-ray crystallography and chimeric analyses combined with site-directed mutagenesis of avian and mammalian cognates revealed that a Met to Val change at residue 417 was sufficient to switch the human and chick phenotype. These results establish that the genetic drive to evolve a novel and functionally selectable receptor can be modulated by a single amino acid change and suggest how nuclear receptors can accommodate natural variation in species physiology.

Amino Acid Substitution↗
PubMed2004

Roles of PPAR delta in lipid absorption and metabolism: a new target for the treatment of type 2 diabetes.

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors exerting several functions in development and metabolism. PPARalpha, activated by polyunsaturated fatty acids and fibrates, is implicated in regulation of lipid metabolism, lipoprotein synthesis and metabolism and inflammatory response in liver and other tissues. PPARgamma plays important roles in regulation of proliferation and differentiation of several cell types, including adipose cells. Its activation by thiazolidinediones results in insulin sensibilization and antidiabetic action. Until recently, the physiological functions of PPARdelta remain elusive. The utilization of specific agonists and of appropriate cellular and animal models revealed that PPARdelta has an important role in metabolic adaptation of several tissues to environmental changes. Treatment of obese animals by specific PPARdelta agonists results in normalization of metabolic parameters and reduction of adiposity. The nuclear receptor appeared to be implicated in the regulation of fatty acid burning capacities of skeletal muscle and adipose tissue by controlling the expression of genes involved in fatty acid uptake, beta-oxidation and energy uncoupling. PPARdelta is also implicated in the adaptive metabolic response of skeletal muscle to endurance exercise by controlling the number of oxidative myofibers. Given the results obtained with animal models, PPARdelta agonists may have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption in skeletal muscle and adipose tissue.

Adipose Tissue↗