PPAR Agonists (ppar + agonist)

Distribution by Scientific Domains


Selected Abstracts


The role of intramuscular lipid in insulin resistance

ACTA PHYSIOLOGICA, Issue 4 2003
B. D. Hegarty
Abstract There is interest in how altered lipid metabolism could contribute to muscle insulin resistance. Many animal and human states of insulin resistance have increased muscle triglyceride content, and there are now plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic glucose,fatty acid cycle. We postulate that muscle cytosolic accumulation of the metabolically active long-chain fatty acyl CoAs (LCACoA) is involved, leading to insulin resistance and impaired insulin signalling or impaired enzyme activity (e.g. glycogen synthase or hexokinase) either directly or via chronic translocation/activation of mediators such as a protein kinase C (particularly PKC , and ,). Ceramides and diacylglycerols (DAGs) have also been implicated in forms of lipid-induced muscle insulin resistance. Dietary lipid-induced muscle insulin resistance in rodents is relatively easily reversed by manipulations that lessen cytosolic lipid accumulation (e.g. diet change, exercise or fasting). PPAR agonists (both , and ,) also lower muscle LCACoA and enhance insulin sensitivity. Activation of AMP-activated protein kinase (AMPK) by AICAR leads to muscle enhancement (especially glycolytic muscle) of insulin sensitivity, but involvement of altered lipid metabolism is less clear cut. In rodents there are similarities in the pattern of muscle lipid accumulation/PKC translocation/altered insulin signalling/insulin resistance inducible by 3,5-h acute free fatty acid elevation, 1,4 days intravenous glucose infusion or several weeks of high-fat feeding. Recent studies extend findings and show relevance to humans. Muscle cytosolic lipids may accumulate either by increased fatty acid flux into muscle, or by reduced fatty acid oxidation. In some circumstances muscle insulin resistance may be an adaptation to optimize use of fatty acids when they are the predominant available energy fuel. The interactions described here are fundamental to optimizing therapy of insulin resistance based on alterations in muscle lipid metabolism. [source]


Discordance between intramuscular triglyceride and insulin sensitivity in skeletal muscle of Zucker diabetic rats after treatment with fenofibrate and rosiglitazone

DIABETES OBESITY & METABOLISM, Issue 5 2007
K. J. Nadeau
Aim:, Intramyocellular triglyceride (IMTG) correlates with insulin resistance, but there is no clear causal relationship. Insulin resistance and associated hyperinsulinaemia may increase IMTG, via the insulin-regulated transcription factor, sterol regulatory element,binding protein 1 (SREBP-1). PPAR agonists may also affect IMTG via changes in insulin sensitivity, SREBP-1 or other factors. Methods:, We examined skeletal muscle IMTG and SREBP-1 expression, and metabolic parameters in Zucker diabetic fatty rats (ZDF) after 25 weeks of PPAR-, or PPAR-, administration. Results:, Compared with Zucker lean rats (ZL), untreated ZDF had significantly higher weights, serum glucose, insulin, free fatty acids, total cholesterol and triglycerides. IMTG and SREBP-1c messenger RNA (mRNA) were also higher in untreated ZDF; both were decreased by fenofibrate (FF). Rosiglitazone (Rosi), despite marked improvement in glycaemia, hyperinsulinaemia and hyperlipidaemia, failed to affect SREBP-1 expression, and increased body weight and IMTG. Rosi/FF combination caused less weight gain and no IMTG increase, despite metabolic effects similar to Rosi alone. Conclusions:, IMTG and SREBP-1c mRNA are high in the ZDF. FF and Rosi both improved insulin sensitivity but had opposite effects on IMTG. Thus, there was a clear discordance between insulin sensitivity and IMTG with PPAR agonists, indicating that IMTG and insulin sensitivity do not share a simple relationship. [source]


PPAR, and PPAR, effectively protect against HIV-induced inflammatory responses in brain endothelial cells

JOURNAL OF NEUROCHEMISTRY, Issue 2 2008
Wen Huang
Abstract Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which down-regulate inflammatory signaling pathways. Therefore, we hypothesized that alterations of PPAR functions can contribute to human immunodeficiency virus-1 (HIV-1)-induced dysfunction of brain endothelial cells. Indeed, treatment with HIV-1 transactivator of transcription (Tat) protein decreased PPAR transactivation in brain endothelial cells. We next stably over-expressed PPAR, and PPAR, in a newly developed cell line of human brain endothelial cells (hCMEC/D3 cells). Tat-induced up-regulation of inflammatory mediators, such as interleukin (IL)-1,, tumor necrosis factor-,, CCL2, and E-selectin were markedly attenuated in hCMEC/D3 over-expressing PPAR, or PPAR,. These results were confirmed in CCL2 and E-selectin promoter activity studies. Similar protective effects were observed in hCMEC/D3 after activation of PPAR, by exogenous PPAR agonists (dPGJ2 and rosiglitazone). PPAR over-expression also prevented Tat-induced binding activity and transactivation of nuclear factor-,B. Importantly, increased PPAR activity attenuated induction of IL-1,, tumor necrosis factor-,, CCL2, and E-selectin in hCMEC/D3 cells co-cultured with HIV-1-infected Jurkat cells. The protective effects of PPAR over-expression were reversed by the antagonists of PPAR, (MK886) or PPAR, (GW9662). The present data suggest that targeting PPAR signaling may provide a novel therapeutic approach to attenuate HIV-1-induced local inflammatory responses in brain endothelial cells. [source]


PPAR: a therapeutic target in Parkinson's disease

JOURNAL OF NEUROCHEMISTRY, Issue 2 2008
Rajnish K. Chaturvedi
Abstract Parkinson's disease (PD) is a progressive and chronic neurodegenerative disorder, characterized by progressive loss of dopaminergic neurons in substantia nigra. The etiology and pathogenesis of PD is still elusive, however, a large body of evidence suggests a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction in the pathogenesis of PD. Due to multifactorial nature of the disease, currently available drug therapy cannot halt / slow down the disease progression, and only provides symptomatic relief. Peroxisome proliferator-activated receptor (PPAR), a member of nuclear receptor superfamily, regulates development, tissue differentiation, inflammation, mitochondrial function, wound healing, lipid metabolism and glucose metabolism. Recently, several PPAR agonists were shown to exert neuroprotective activity against oxidative damage, inflammation and apoptosis in several neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and multiple sclerosis. Similarly, regular intake of PPAR activating non-steroidal anti-inflammatory drugs such as indomethacin and ibuprofen was associated with reduced incidence and progression of neurodegenerative disorders in several epidemiological studies. In this article, we review studies relating to the neuroprotective effect of PPAR agonists in in vitro and in vivo models of PD. Similarly, the pharmacological mechanism in neuroprotective actions of PPAR agonists is also reviewed. In conclusion, PPAR agonists exert neuroprotective actions by regulating the expression of a set of genes involved in cell survival processes, and could be a therapeutic target in debilitating neurodegenerative illnesses such as PD. [source]


Agonists specific for the transcription factor PPARdelta accelerate differentiation of oligodendrocytes

JOURNAL OF NEUROCHEMISTRY, Issue 2002
R. P. Skoff
Peroxisome proliferator activated receptors (PPARs) are transcription factors belonging to the nuclear hormone receptor superfamily that regulate key genes involved in lipid metabolism. PPAR, is ubiquitously expressed at low levels in many tissues and its function has remained elusive. However, we have shown that PPAR, is abundantly expressed in oligodendrocytes (Ols), suggesting this receptor plays a critical role in oligodendrocyte differentiation (Granneman et al. 1998 J. Neurosci. Res51, 563). We first investigated the effects of PPAR agonists on proliferation and differentiation of Ols in tissue culture. Primary glial and enriched Ol cultures were treated with ligands that specifically activate PPAR, and PPAR, (Berger et al. 1999 J. Biol. Chem. 274, 6717). PPAR, but not PPAR, agonists increased the size of OL membrane sheets within 24 h of application. The increase in membrane sheet size was mirrored by increases in MBP and PLP mRNA's. In enriched Ol cultures, the number of Ols was increased 70% with the PPAR, agonist but not the PPAR, agonist (Saluja et al. 2001 Glia33, 191). In vivo injections of PPAR, agonist into P2 and P3 mice show an increase of total macroglia in the ventral and dorsal funiculi of the spinal cord of 20,40% compared to controls. Preliminary observations suggest the Ols in agonist treated cultures are larger and more densely stained than controls. Our results show for the first time that a specific ligand for a transcription factor is capable of activating the program of Ol differentiation. Acknowledgements: Supported by NMSS. [source]


From Molecular Shape to Potent Bioactive Agents I: Bioisosteric Replacement of Molecular Fragments

CHEMMEDCHEM, Issue 1 2009
Ewgenij Proschak
Ligand-based virtual screening: By means of shape- and pharmacophore-based virtual screening, a potent PPAR,-selective activator was identified from a large compound collection with minimal experimental effort. This compound represents a scaffold-hop from known PPAR agonists and provides proof-of-concept for a novel ligand-based virtual screening approach. [source]