gw-501516 and Metabolic-Syndrome

Metabolic syndrome is a disorder described by reduced insulin sensitivity, overweight, hyperlipidaemia, high blood pressure and myocardial disorders, mainly due to high fat diet and lack of physical activity. The peroxisome proliferator activated receptors (PPARs) are type II nuclear hormone receptors that regulate a number of processes in living systems, such as metabolism of carbohydrates and fatty acids, growth and differentiation of cell, and inflammatory reactions. Alpha, gamma and delta are the three distinct isoforms of PPAR. The stimulation of PPARδ alters body's energy fuel preference from glucose to fat. The PPARδ isoform is expressed ubiquitously in all tissues, especially in those tissues which involved in metabolism of lipids like adipose tissue, liver, kidney, and muscle. Currently, PPARδ is an emerging therapeutic target for the pharmacological therapy of disorders associated with metabolic syndrome. Several PPARδ selective agonists had been reported in last ten years, many of them had been advanced into the late phase of clinical trials such as Endurobol (GW501516). However, no PPARδ agonists are yet approved for human use. The present work had been planned to cover wide variety of PPARδ agonists reported till now along with their potential role to tackle various metabolic disorders. The present review has been planned to focus mainly the most popular PPARδ agonists.

Topics: Animals; Humans; Metabolic Syndrome; PPAR delta; Thiazoles

Topics: Animals; Metabolic Syndrome; Mice; PPAR delta; Thiazoles

Topics: Animals; CCAAT-Enhancer-Binding Proteins; DNA-Binding Proteins; Fatty Acids; Glucose Tolerance Test; Humans; Insulin Resistance; Kruppel-Like Transcription Factors; Life Style; Metabolic Syndrome; Mice; Mice, Transgenic; Multigene Family; Muscle, Skeletal; Nuclear Proteins; Oxidation-Reduction; Receptors, Cytoplasmic and Nuclear; Sterol Regulatory Element Binding Protein 1; Thiazoles; Transcription Factors; Transcription, Genetic

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors playing important regulatory functions in development and metabolism. PPARalpha and PPARgamma are the most extensively examined and characterized, mainly because they are activated by marketed hypolipidemic and insulin sensitizer compounds, such as fibrates and thiazolidinediones. It has been established that the third member of the family, PPARdelta is implicated in developmental regulations, but until recently, its role in metabolism remained unclear. The availability of specific PPARdelta agonists and of appropriate cellular and animal models revealed that PPARdelta plays a crucial role in fatty acid metabolism in several tissues. Treatment of obese animals with PPARdelta agonists results in normalization of metabolic parameters and reduction of adiposity. Activation of the nuclear receptor promotes fatty acid burning in skeletal muscle and adipose tissue by upregulation of fatty acid uptake, beta-oxidation and energy uncoupling. PPARdelta is also involved in the adaptive metabolic responses of skeletal muscle to environmental changes, such as long-term fasting or physical exercise, by controlling the number of oxidative myofibers. These observations strongly suggest that PPARdelta agonists may have therapeutic usefulness in metabolic syndrome by increasing fatty acid consumption and decreasing obesity.

Topics: Adipose Tissue; Animals; Fatty Acids; Insulin Resistance; Ligands; Macaca mulatta; Metabolic Syndrome; Muscle, Skeletal; Obesity; PPAR delta; Thiazoles

Peroxisome proliferator-activated receptor-δ-induced upregulation in skeletal muscle fatty acid oxidation would predict the modulation of lipid/lipoproteins.. GW501516 (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 demonstrated HDL cholesterol increases up to 16.9% (10 mg) and apoA-I increases up to 6.6%. Reductions were observed in low-density lipoprotein (LDL) cholesterol (-7.3%), triglycerides (-16.9%), apoB (-14.9%), and free fatty acids (-19.4%). The exploratory study showed significant reductions in the concentration of very LDL (-19%), intermediate-density lipoprotein (-52%), and LDL (-14%, predominantly a reduction in small particles), whereas the number of HDL particles increased (+10%; predominantly medium and large HDL).. GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. These data are consistent with peroxisome proliferator-activated receptor-δ being a potentially important target for providing cardiovascular protection in metabolic syndrome-like patients.

Topics: Adult; Analysis of Variance; Apolipoprotein A-I; Apolipoproteins B; Biomarkers; Blood Glucose; Chi-Square Distribution; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Double-Blind Method; Dyslipidemias; Fatty Acids, Nonesterified; Female; Humans; Hypolipidemic Agents; Insulin; Male; Metabolic Syndrome; Middle Aged; PPAR gamma; Thiazoles; Time Factors; Treatment Outcome; Triglycerides

Topics: AMP-Activated Protein Kinases; Animals; Fatty Acids; Hypertriglyceridemia; Immunoblotting; Liver; Metabolic Syndrome; Mice; Nuclear Proteins; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphatidate Phosphatase; Phosphorylation; PPAR alpha; PPAR gamma; PPAR-beta; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Thiazoles; Trans-Activators; Transcription Factors; Triglycerides

We evaluated the effects of GW501516, a specific peroxisome proliferator-activated receptor beta/delta (PPARdelta) agonist in metabolic syndrome mice, obtained by perinatal injection of monosodium L-glutamate, to investigate the efficacy of GW501516 against metabolic syndrome and the effectiveness of PPARdelta activation as therapeutic target for metabolic syndrome. After 14 days treatment, GW501516 effectively improved the glucose intolerance, normalized the fasted blood glucose, and increased the serum high-density lipoprotein cholesterol (HDL-C) level. Postprandial blood glucose, serum insulin, leptin, free fatty acid (FFA) levels, and total cholesterol/HDL-C ratio were also significantly decreased. Moreover, semiquantitative reverse transcription-polymerase chain reaction results indicated that the above phenotypes might be due to (i) enhancement of fatty acid oxidation in muscle, adipose tissue and the liver; (ii) improvement of insulin-stimulated glucose transportation in skeletal muscle and adipose tissue; and (iii) reduced local glucocorticoid synthesis. Therefore, GW501516 could significantly ameliorate dyslipidaemia and insulin resistance in monosodium L-glutamate mice and activation of PPARdelta could be envisioned as a useful strategy against human metabolic syndrome and related diseases.

Topics: Animals; Animals, Newborn; Blood Glucose; Cholesterol, HDL; Dyslipidemias; Fatty Acids; Gene Expression; Insulin; Insulin Resistance; Leptin; Metabolic Syndrome; Mice; Mice, Obese; Oxidation-Reduction; PPAR delta; Sodium Glutamate; Thiazoles

In this study, we defined the role of peroxisome proliferator-activated receptor beta/delta (PPARdelta) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARdelta subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARdelta controls fatty acid oxidation by regulating genes involved in fatty acid transport, beta-oxidation, and mitochondrial respiration. Similar PPARdelta-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid beta-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid beta-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARdelta is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.

Topics: Animals; Dimethyl Sulfoxide; Enzymes; Fatty Acids, Nonesterified; Insulin Resistance; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Oxidation-Reduction; Rats; Receptors, Cytoplasmic and Nuclear; Thiazoles; Transcription Factors