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

Cardiovascular disease (CVD) remains the leading cause of mortality in developed countries. Several risk factors are associated with CVD, including type 2 diabetes, obesity, insulin resistance, dyslipidaemia and hypertension. Different pharmacological therapies have been developed to control these risk factors. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which belong to the nuclear receptor superfamily that controls lipid and glucose metabolism as well as inflammatory risk factors for CVD. PPARalpha agonists, such as the fibrates, correct dyslipidaemia, thus decreasing CVD risk. PPARgamma agonists, such as the glitazones, increase insulin sensitivity and decrease plasma glucose levels in patients with diabetes. Moreover, both PPARalpha and PPARgamma agonists exert anti-inflammatory activities in liver, adipose and vascular tissues. In this review, we focus on the mode of action of PPARalpha and PPARalpha agonists, illustrating the potential of the newly developed dual PPAR agonists for the treatment of global risk in patients with the metabolic syndrome or type 2 diabetes.
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PMID:Inflammation, dyslipidaemia, diabetes and PPars: pharmacological interest of dual PPARalpha and PPARgamma agonists. 1603 93

The nuclear receptor superfamily consists of 48 mammalian transcription factors that regulate nearly all aspects of development, inflammation, and metabolism. Two subclasses, the Peroxisome Proliferator-Activated Receptors (PPARs) and Liver X Receptors (LXRs), are lipid-sensing receptors that have critical roles in lipid and glucose metabolism. The parallel epidemics of obesity and diabetes shine a spotlight on the potential for therapeutic manipulation of PPARs and LXRs to combat these diseases. In recognition of this, a recent Keystone Symposium was devoted to these metabolic receptors. Here, we summarize some of the major highlights and future projections discussed at the meeting.
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PMID:Gaining weight: the Keystone Symposium on PPAR and LXR. 1607 2

Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARgamma agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown recently that PPARgamma agonists ameliorate experimental allergic encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). We have further shown that PPARgamma agonists inhibit EAE through blocking IL-12 signaling leading to Th1 differentiation and the PPARgamma-deficient heterozygous mice (PPARgamma(+/-)) develop an exacerbated EAE. In this study, we show that in vivo treatment (i.p.) with 100 mug PPARgamma antagonists, Bisphenol A diglycidyl ether (BADGE) or 2-Chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907), on every other day from day 0 to 30, increased the severity and duration of EAE in C57BL/6 wild-type and PPARgamma(+/-) mice. The exacerbation of EAE by PPARgamma antagonists associates with an augmented neural antigen-induced T cell proliferation, IFNgamma production or Th1 differentiation. These results further suggest that PPARgamma is a critical physiological regulator of CNS inflammation and demyelination in EAE.
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PMID:PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. 1609 Dec 93

A variety of adipocytokines and peptides secreted from adipocytes have been considered to play a crucial role in obesity, insulin resistance, and type 2 diabetes. Recently, visfatin, a new adipocytokine, known as a pre-B cell colony-enhancing factor, has been isolated from visceral fat deposits. It has been shown to activate insulin receptors in a manner different from insulin. To understand the role of adipocytokines in improving insulin sensitivity via activation of the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and -gamma (PPAR-gamma), we examined the expression of visfatin, adiponectin, and TNF-alpha in visceral fat depots of Otsuka Long-Evans Tokushima fatty (OLETF) rats from early to advanced diabetic stage (from 28 to 40 weeks of age). Serum glucose and insulin concentrations significantly (P<0.05) decreased in rosiglitazone or fenofibrate-treated OLETF rats compared to untreated OLETF rats. Rosiglitazone significantly increased serum adiponectin concentration from 20 to 40 weeks of age (P<0.05), whereas fenofibrate reduced TNF-alpha concentration. The expression of visfatin and adiponectin mRNA in visceral fat deposits was elevated by rosiglitazone or fenofibrate treatments when compared to untreated OLETF rats (P<0.05), whereas, TNF-alpha mRNA was down-regulated by these drugs (P<0.05). These results suggest that rosiglitazone and fenofibrate may prevent type 2 diabetes by regulating adipocytokines including visfatin, adiponectin, and TNF-alpha.
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PMID:Effect of PPAR-alpha and -gamma agonist on the expression of visfatin, adiponectin, and TNF-alpha in visceral fat of OLETF rats. 1615 99

Fibric acid is a synthetic ligand of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-alpha that is highly expressed in skeletal muscle and heart, where it promotes beta-oxidation of fatty acids to mediate hypolipidemic actions. PPAR-alpha regulates expression of key proteins involved in atherogenesis, vascular inflammation, plaque instability, and thrombosis. Thus, PPAR-alpha may exert direct antiatherogenic actions in the vascular wall. Endothelial dysfunction associated with the metabolic syndrome and other insulin-resistant states is characterized by impaired insulin-stimulated nitric oxide production from the endothelium and decreased blood flow to skeletal muscle. Thus, improvement in insulin sensitivity leads to improved endothelial function. This may be an additional mechanism whereby fibrates decrease the incidence of coronary heart disease. Adiponectin is a protein secreted specifically by adipose cells that may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance. In this review, we discuss the mechanisms underlying the vascular and metabolic effects of fibrates that may act synergistically to prevent or regress atherosclerosis and coronary heart disease.
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PMID:Beneficial vascular and metabolic effects of peroxisome proliferator-activated receptor-alpha activators. 1623 May 15

Lipids are essential components of biological membranes, fuel molecules and metabolic regulators that control cellular functions, metabolism and homeostasis. The liver plays a central role in regulating lipid metabolism and whole body lipid homeostasis. Sterols, bile acids and fatty acids are the endogenous ligands of the liver orphan receptor, farnesoid X receptor, peroxisome proliferator-activated receptor, vitamin D receptor, constitutive androstane receptor and pregnane X receptor. These metabolic receptors coordinately regulate lipid, glucose, energy and drug metabolism. Alteration of lipid homeostasis causes dyslipidemia, which is a major risk factor contributing to atherosclerotic cardiovascular diseases, diabetes, obesity and liver diseases. Advances in the understanding of the mechanisms of nuclear receptor regulation of lipid homeostasis have provided an opportunity to investigate potential therapeutic drugs targeted to nuclear receptors. This could be useful for the treatment of diabetes, and cardiovascular and chronic liver diseases.
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PMID:Nuclear receptor regulation of lipid metabolism: potential therapeutics for dyslipidemia, diabetes, and chronic heart and liver diseases. 1625 20

In addition to their role in cell cycle progression, new data reveal an emerging role of D-type cyclins in transcriptional regulation and cellular differentiation processes. Using 3T3-L1 cell lines to study adipogenesis, we observed an up-regulation of cyclin D3 expression throughout the differentiation process. Surprisingly, cyclin D3 was only minimally expressed during the initial stages of adipogenesis, when mitotic division is prevalent. This seemingly paradoxical expression led us to investigate a potential cell cycle-independent role for cyclin D3 during adipogenesis. We show here a direct interaction between cyclin D3 and the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). Our experiments reveal cyclin D3 acts as a ligand-dependent PPARgamma coactivator, which, together with its cyclin-dependent kinase partner, phosphorylates the A-B domain of the nuclear receptor. Overexpression and knockdown studies with cyclin D3 had marked effects on PPARgamma activity and subsequently on adipogenesis. Chromatin immunoprecipitation assays confirm the participation of cyclin D3 in the regulation of PPARgamma target genes. We show that cyclin D3 mutant mice are protected from diet-induced obesity, display smaller adipocytes, have reduced adipogenic gene expression, and are insulin sensitive. Our results indicate that cyclin D3 is an important factor governing adipogenesis and obesity.
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PMID:Cyclin D3 promotes adipogenesis through activation of peroxisome proliferator-activated receptor gamma. 1626 Jun 12

The small heterodimer partner (SHP) is an atypical nuclear receptor lacking the N-terminal ligand-independent activation domain and the DNA binding domain. SHP acts as transcriptional inhibitor of a large set of nuclear receptors, among which ER, AR, CAR, RXR, GR, LXR and ERRgamma. The repression mechanism of SHP involves several actions including competition with coactivators binding on the AF-2 of nuclear receptors and recruitment of transcriptional inhibitors such as EID-1. The investigation of the structure and repression mechanism of SHP is a challenging task for a full understanding of nuclear receptor interaction pathways and functions. So far, mutational analyses in multiple populations identified loss of function mutants of SHP gene involved in mild obesity, increased birth weight and insulin levels. Furthermore, experimental mutagenesis has been exploited to characterize the interactions between SHP and the transcriptional inhibitor EID-1. With the aim of gaining insight into the structural basis of SHP repression mechanism, we modelled SHP and EID-1 structures. Docking experiments were carried out to identify the EID-1 binding surface on SHP structure. The results obtained in this study allow for the first time a unique interpretation of many experimental data available from the published literature. In addition, a fascinating hypothesis raises from the inspection of the proposed SHP structure: the presence of a potential unexpected ligand binding site, supported by recently available experimental data that may represent a breakthrough in the design and development of synthetic modulators of SHP functions.
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PMID:Unveiling hidden features of orphan nuclear receptors: the case of the small heterodimer partner (SHP). 1628 80

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The activation of PPAR-gamma, an isotype of PPARs, can either increase or decrease the transcription of target genes. The genes controlled by this form of PPAR have been shown to encode proteins or peptides that participate in the pathogenesis of insulin resistance. Insulin resistance is defined as a state of reduced responsiveness to normal circulating concentrations of insulin and it often co-exists with central obesity, hypertension, dyslipidemia, and atherosclerosis. There is substantial evidence that links obesity with insulin resistance and type-2 diabetes. The early phase of obesity-related insulin resistance has 2 components: (a) interruption of lipid homeostasis leading to the increased plasma concentration of fatty acids that is normally suppressed by the activation of PPAR-gamma, and (b) activation of factors such as cytokines depressed by PPAR-gamma that cause insulin resistance. Therefore, it is logical to suggest that activation of PPAR-gamma may partially reverse the state of insulin resistance. Evidently, activation of the nuclear receptor, PPAR-gamma, by thiazolidinediones has been reported to ameliorate insulin resistance. Although hepatotoxity and possibility to induce congestive heart failure (CHF) limit the widely use of thiazolodinediones, they are still powerful weapon to fight against insulin resistance and type-2 diabetes if use properly. This article reviews the physiology of PPAR-gamma and insulin-signaling transduction, the pathogenesis of insulin resistance in obesity-related type-2 diabetes, the pharmacological role of PPAR-gamma in insulin resistance, and additional effects of thiazolidinediones.
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PMID:Peroxisome proliferator-activated receptor gamma as a drug target in the pathogenesis of insulin resistance. 1630 9

Nuclear receptors are transcription factors that are essential in embryonic development, maintenance of differentiated cellular phenotypes, metabolism, and apoptosis. Dysfunction of nuclear receptor signaling leads to a wide spectra of proliferative, reproductive, and metabolic diseases, including cancers, infertility, obesity, and diabetes. In addition, many proteins have been identified as coregulators which can be recruited by DNA-binding nuclear receptors to affect transcriptional regulation. The cellular level of coregulators is crucial for nuclear receptor-mediated transcription and many coregulators have been shown to be targets for diverse intracellular signaling pathways and posttranslational modifications. This review provides a general overview of the roles and mechanism of action of nuclear receptors and their coregulators. Since progression of renal diseases is almost always associated with inflammatory processes and/or involve metabolic disorders of lipid and glucose, cell proliferation, hypertrophy, apoptosis, and hypertension, the importance of nuclear receptors and their coregulators in these contexts will be addressed.
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PMID:Nuclear receptors and their coregulators in kidney. 1631 22


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