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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Only a limited number of treatment options are available for insulin resistance, a major cause of type 2 diabetes (T2D) and the metabolic syndrome. None adequately address the simultaneous defects in lipid and carbohydrate metabolism. Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors that function as ligand-activated transcription factors. The PPAR family, which includes PPARalpha, PPARgamma, and PPARdelta, are receptors for fatty acids and their metabolites. Consequently, PPARs play a critical physiological role in the regulation of genes involved in glucose, fatty acid, and cholesterol metabolism. PPARalpha and PPARgamma also mediate anti-inflammatory effects, which likely contribute to their anti-atherogenic activities. A number of PPAR agonist drugs are marketed for the treatment of individual aspects of the metabolic syndrome. Dual agonists that target both PPARalpha and PPARgamma are being developed in an effort to broaden the activities and beneficial effects of the ligands selective for PPARgamma. To address the multiple metabolic defects associated with insulin resistance, T2D and the metabolic syndrome, the simultaneous activation of PPARalpha, PPARgamma, and PPARdelta by a single compound (i.e. a PPAR pan-agonist) is being pursued. Similar to PPARalpha and PPARgamma, PPARdelta plays a significant role in the regulation of genes that control lipid metabolism. Unlike PPARgamma, PPARdelta is not adipogenic, and activation of PPARdelta is associated with an anti-obesity and more insulin-sensitive phenotype. While there are no currently marketed drugs known to target PPARdelta, pre-clinical studies indicate that PPARdelta agonists increase energy expenditure and elevate plasma high-density lipoprotein (HDL) cholesterol. Recent studies in rodents and primates suggest that a small molecule targeting all three isoforms of PPAR would provide a significantly improved treatment option.
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PMID:Novel approach to treat insulin resistance, type 2 diabetes, and the metabolic syndrome: simultaneous activation of PPARalpha, PPARgamma, and PPARdelta. 1822 Jun 6

Peroxisome proliferator-activated receptor (PPAR)-delta is a transcription factor that belongs to the PPAR family. PPAR-delta is abundantly expressed in the heart, and its role in the heart is largely unknown. We tested whether pharmacological activation of PPAR-delta protects the heart from ischemia/reperfusion (I/R) injury in male Zucker fatty rats, a rodent model of obesity and dyslipidemia. A highly selective PPAR-delta agonist, [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl] thio]-2-methylphenoxy]acetic acid (GW0742), was administered for 7 days at 10 mg/kg/day (p.o., once a day). Ischemic injury was produced by occlusion of the left anterior descending artery for 30 min followed by reperfusion for up to 24 h. Treatment with GW0742 reduced serum levels of cardiac troponin-I and infarct size by 63% (p < 0.01) and 32% (p < 0.01), respectively, and improved left ventricular function. Treatment with GW0742 up-regulated gene expression involved in cardiac fatty acid oxidation, increased fat use in the heart, and reduced serum levels of free fatty acids. The enhanced cardiac expression of interleukin (IL)-6, IL-8, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 induced by I/R were significantly attenuated by GW0742. Treatment with GW0742 also reduced apoptotic cardiomyocytes by 34% and cardiac caspase-3 activity by 61% (both p < 0.01 versus vehicle). GW0742 differentially regulated Bcl family members, favoring cell survival, and attenuated I/R-induced cardiac mitochondrial damage. In addition, GW0742 treatment augmented the cardiac Akt signaling pathway, as reflected by enhanced phospho-3-phosphoinositide-dependent kinase-1 and p-Akt. The results indicate that activation of PPAR-delta protected the heart from I/R injury in Zucker fatty rats, and multiple mechanisms including amelioration of lipotoxicity, anti-inflammation, and up-regulation of prosurvival signaling contribute together to the cardioprotection.
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PMID:In vivo activation of peroxisome proliferator-activated receptor-delta protects the heart from ischemia/reperfusion injury in Zucker fatty rats. 1828 12

Peroxisome proliferator-activated receptor (PPAR)gamma, a transcription factor belonging to the nuclear receptor superfamily, is essential for adipogenesis. PPARgamma is recognized as a major target for the insulin-sensitizing effects of the thiazolidinediones. Previous studies have demonstrated that heterozygous PPARgamma-deficient mice are protected from high-fat diet (HFD)-induced adipocyte hypertrophy, obesity and insulin resistance, which suggests that PPARgamma may have a pivotal role in adipocyte hypertrophy, obesity and insulin resistance. In this study, we generated transgenic mice with the gain-of-function PPARgamma Ser112Ala mutation (S112A mice) using the aP2 promoter, to elucidate the impact of increased PPARgamma activity in mature adipocytes. Despite a 2-3-fold increase in the adipocyte PPARgamma2 gene expression and PPARgamma activity, the S112A mice showed comparable adiposity and insulin sensitivity to wild-type mice under both normal and HFD conditions. Although the expression levels of the PPARgamma target genes involved in lipid metabolism, such as aP2 and stearoyl-CoA desaturase 1, were upregulated in the white adipose tissue of the S112A mice, the serum levels of free fatty acid, triglyceride, adiponectin and leptin, as well as the oxygen consumption, were comparable between the wild-type and S112A mice under the HFD condition. Moreover, treatment with rosiglitazone ameliorated insulin resistance and glucose intolerance to a similar degree in the two genotypes under the HFD condition. In conclusion, whereas the 50% decrease in PPAR gamma activity showed protection from HFD-induced obesity and insulin resistance, in the present study, the 2-3-fold increase in PPARgamma2 expression and PPARgamma activity failed to show obesity and insulin resistance even under the HFD condition.
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PMID:Impact of increased PPARgamma activity in adipocytes in vivo on adiposity, insulin sensitivity and the effects of rosiglitazone treatment. 1850 83

Peroxisome proliferator-activated receptor-alpha (PPARA) has been shown to increase fatty acid oxidation and decrease cytokine levels and has been implicated in insulin production. Genetic variants of PPARA have been associated with cardiovascular disease, obesity and type II diabetes mellitus. Although no research to date has investigated the possible link between PPARA and breast cancer, the function of this gene suggests that it could play a role in breast cancer development. Six PPARA polymorphisms were evaluated in association with incident breast cancer in a population-based case-control study (n = 1073 cases and n = 1112 controls) using unconditional logistic and multilevel regression and haplotype-based analyses. The odds of breast cancer were doubled among women with PPARA polymorphism rs4253760 (odds ratio = 1.97 for rare versus common homozygote alleles; 95% confidence interval: 1.14, 3.43). This association remained constant with the inclusion of all interrogated polymorphisms studied in hierarchical models. No additive interactions with body mass index or weight gain were present, but there was some evidence of interaction between PPARA variants and aspirin use, defined as use at least once per week for 6 months or longer. Fourteen haplotypes were imputed with frequencies >1% among postmenopausal women, but no statistically significant differences in haplotype frequencies between cases and controls were evident. Our results are the first to evaluate the relationship between PPARA and breast cancer incidence and suggest that replication in an independent cohort is warranted.
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PMID:Peroxisome proliferator-activated receptor-alpha (PPARA) genetic polymorphisms and breast cancer risk: a Long Island ancillary study. 1858 86

Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha) is a multifunctional transcriptional regulator for the pathways controlling mitochondrial biogenesis, oxidative metabolism, and glucose homeostasis. Genetic studies have suggested that Gly482Ser polymorphism of the PGC-1alpha gene is associated with a higher risk of type 2 diabetes, obesity, and hypertension. Adiponectin is an antidiabetic and antiatherogenic adipocytokine that is specifically produced by adipose tissue, and the transcription of the adiponectin gene is regulated by PPARgamma. In this study, we examined the effect of Gly482Ser polymorphism on the plasma adiponectin level in Japanese type 2 diabetics. The Gly482Ser genotype was associated with a lower plasma adiponectin level in type 2 diabetic men, but not in type 2 diabetic women. The impact of this variation on the adiponectin promoter was also assessed by a reporter gene assay, but there was no significant difference between activation by the wild type and Gly482Ser- PGC-1alpha proteins, indicating that this variation itself has no functional effect. Evaluation of the pattern of linkage disequilibrium revealed that the Gly482Ser polymorphism is located in the largest linkage disequilibrium block of the PGC-1alpha gene. Therefore the observed gender-specific association between PGC-1alpha and the plasma adiponectin level may reflect linkage disequilibrium of Gly482Ser polymorphism with other causative variations.
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PMID:PGC-1alpha Gly482Ser polymorphism is associated with the plasma adiponectin level in type 2 diabetic men. 1861 52

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor family of ligand-activated transcription factors. This subfamily is composed of three members-PPARalpha, PPARdelta, and PPARgamma-that differ in their cell and tissue distribution as well as in their target genes. PPARalpha is abundantly expressed in liver, brown adipose tissue, kidney, intestine, heart, and skeletal muscle; and its ligands have been used to treat diseases such as obesity and diabetes. The recent finding that members of the PPAR family, including the PPARalpha, are expressed by tumor and endothelial cells together with the observation that PPAR ligands regulate cell growth, survival, migration, and invasion, suggested that PPARs also play a role in cancer. In this review, we focus on the contribution of PPARalpha to tumor and endothelial cell functions and provide compelling evidence that PPARalpha can be viewed as a new class of ligand activated tumor "suppressor" gene with antiangiogenic and antitumorigenic activities. Given that PPAR ligands are currently used in medicine as hypolipidemic drugs with excellent tolerance and limited toxicity, PPARalpha activation might offer a novel and potentially low-toxic approach for the treatment of tumor-associated angiogenesis and cancer.
PPAR Res 2008
PMID:PPARalpha Ligands as Antitumorigenic and Antiangiogenic Agents. 1872 83

Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested positive in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compounds 5, 7, and 8 were identified as PPAR-alpha agonists, whereas compounds 2 and 9 showed agonistic activity for hPPAR-gamma. Moreover, compound 9 was identified as a PPAR-delta antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidaemia, and type 2 diabetes.
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PMID:Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening. 1882 46

Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonism potently reduces circulating triglycerides (TG) in rodents and more modestly so in humans. This study aimed to quantify in vivo the relative contribution of hepatic VLDL-TG secretion and tissue-specific TG clearance to such action. Rats were fed an obesogenic diet, treated with the PPARgamma full agonist COOH (30 mg.kg(-1).day(-1)) for 3 wk, and studied in both the fasted and refed (fat-free) states. Hepatic VLDL-TG secretion rate was not affected by chronic COOH in the fasted state and was only modestly decreased (-30%) in refed rats. In contrast, postprandial VLDL-TG clearance was increased 2.6-fold by COOH, which concomitantly stimulated adipose tissue TG-derived lipid uptake and one of its major determinants, lipoprotein lipase (LPL) activity, in a highly depot-specific manner. TG-derived lipid uptake and LPL were indeed strongly increased in subcutaneous inguinal white adipose tissue and in brown adipose tissue, independently of the nutritional state, whereas of the three visceral fat depots examined (epididymal, retroperitoneal, mesenteric) only the latter responded consistently to COOH. Robust correlations (0.5 < r < 0.9) were observed between TG-derived lipid uptake and LPL in adipose tissues. The agonist did not increase LPL in muscle, and its enhancing action on postprandial muscle lipid uptake appeared to be mediated by post-LPL processes involving increased expression of fatty acid binding/transport proteins (aP2, likely in infiltrated adipocytes, FAT/CD36, and FATP-1). The study establishes in a diet-induced obesity model the major contribution of lipid uptake by specific, metabolically safe adipose depots to the postprandial hypotriglyceridemic action of PPARgamma agonism, and suggests a key role for LPL therein.
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PMID:Tissue-specific postprandial clearance is the major determinant of PPARgamma-induced triglyceride lowering in the rat. 1897 52

The prevalence of obesity in the USA and worldwide has reached epidemic proportions during the last two decades. Drugs currently available for the treatment of obesity provide no more than 5% placebo-adjusted weight loss and are associated with undesirable side effects. Peroxisome proliferator-activated receptor (PPAR) modulators offer potential benefits for the treatment of obesity and its associated complications but their development has been complicated by biological, technical, and regulatory challenges. Despite significant challenges, PPAR modulators are attractive targets for the treatment of obesity and could offer a viable alternative to the millions of patients who fail to lose weight following rigorous dieting and exercise protocols. In addition, PPAR modulators have the potential-added benefit of ameliorating the associated comorbidities.
PPAR Res 2008
PMID:PPARdelta Agonism for the Treatment of Obesity and Associated Disorders: Challenges and Opportunities. 1898 68

Peroxisome proliferator-activated receptors (PPARs) are drug targets for several perturbations of metabolic syndrome, defined as the coexistence of obesity, hyperglycemia, hypertension, and hyper/dyslipidemia. In this study, PPAR activation by oregano (e.g., Origanum vulgare) and its components was tested. Oregano extracts bind but do not transactivate PPARgamma, and binding affinity differs among different oregano extracts. The extracts contain PPARgamma antagonists (e.g., quercetin, luteolin, rosmarinic acid, and diosmetin), selective PPARgamma modulators (e.g., naringenin and apigenin), and PPARgamma agonists (e.g., biochanin A). Oregano extract and isolated compounds in the extract antagonize rosiglitazone-mediated DRIP205/TRAP220 recruitment to PPARgamma, pointing to oregano extracts as putative food supplements for weight reduction. Rosmarinic acid and biochanin A, PPARalpha agonists, may ameliorate the lipid profile. By endothelial nitric oxide synthase activation, oregano extract could prevent atherosclerosis. The results warrant further investigation of oregano extract for its potential to prevent and ameliorate metabolic syndrome and its complications.
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PMID:Oregano: a source for peroxisome proliferator-activated receptor gamma antagonists. 1905 89


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