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

Peroxisome proliferator-activated receptors (PPARs) alpha, gamma and delta (beta) are ligand-activated transcription factors of the nuclear hormone receptor superfamily which have been shown to play key roles in maintaining glucose and lipid homeostasis. The physiological effects of several marketed drugs for the treatment of dyslipidemia (fenofibrate and gemfibrozil) and diabetes (rosiglitazone and pioglitazone) have now been shown to be mediated through PPARalpha and PPARgamma respectively. Over the past few years our understanding of how PPAR ligands and receptors modulate gene expression has greatly increased; this knowledge is being used to design even more potent and efficacious PPAR ligands for the treatment of diabetes, dyslipidemia, atherosclerosis and obesity. This review is a brief survey of the PPAR field which highlights recent progress, with an emphasis on new ligands with novel PPAR profiles, particularly compounds which are co-agonists of PPAalpha, gamma and beta (delta).
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PMID:PPARs as targets for metabolic and cardiovascular diseases. 1610 10

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. The 3 PPAR isotypes, PPAR-alpha, PPAR-gamma, and PPAR-delta, play a key role in the regulation of lipid and glucose metabolism. Obesity and the interrelated disorders of the metabolic syndrome have become a major worldwide health problem. In this review, we summarize the critical role of PPARs in regulating inflammation, lipoprotein metabolism, and glucose homeostasis and their potential implications for the treatment of obesity, diabetes, and atherosclerosis.
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PMID:Obesity, peroxisome proliferator-activated receptor, and atherosclerosis in type 2 diabetes. 1655 57

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

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARgamma is the most extensively studied amongst the three subtypes (alpha, delta and gamma). This receptor is a key modulator of lipid and glucose homeostasis and is predominantly expressed in adipose tissue. Expression of PPARgamma is also found in non-adipose tissues including heart, kidney, spleen, and interestingly, in all relevant components of the vasculature: endothelial and smooth muscle cells. These receptors may therefore also play a role in the regulation of vascular tone and blood pressure. Genetic variants of PPARgamma have also been associated with features of the metabolic syndrome, including obesity and increased blood pressure. The discovery of synthetic ligands for PPARgamma, the Thiazolidinediones (TZDs) has greatly enhanced our understanding of their ligand dependent activation and more importantly their role in vascular pathobiology. Approximately 10 years ago, serendipitous animal experiments demonstrated that despite causing sodium retention, the TZDs actually lowered blood pressure. This review will highlight the role of TZDs in various models of hypertension and discuss their potential role in the management of obesity-related hypertension.
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PMID:Can PPARgamma agonists have a role in the management of obesity-related hypertension? 1671 64

Obesity is frequently accompanied by insulin resistance, type II diabetes, hypertension and atherosclerosis, a cluster of pathologies that are the major components of the metabolic syndrome. Obesity is a known cause for renal dysfunction that leads to two major renal pathologies: hypertension and glomerular and tubulointerstitial injury. Peroxizome proliferator activated receptors (PPARs) are transcription factors belonging to the nuclear hormone receptor superfamily with important functions in the regulation of metabolism. The role of PPARgamma isoforms in adipogenesis and vascular inflammation associated to obesity has been vastly studied and is well recognized, albeit not completely mechanistically understood. Also, the effect of various PPARgamma agonists on blood pressure reduction in different forms of hypertension, including obesity related hypertension has been reported, but the mechanisms involved are only beginning to be studied. Even less clear is the concurrent beneficial effect of PPARgamma agonists thiazolinendiones (TZD) on blood pressure reduction in different forms of hypertension and, at the same time, in some cases, the significant water retention leading to edema and heart failure. The occurrence of both these apparently opposite effects on the renal water and sodium handling suggests a complex role of PPARgamma in the kidney that is likely related to the metabolic state. Also, PPARgamma activation leads to a reduction in mesangial cell proliferation while stimulating apoptosis. TZD treatment reduces albuminuria in obese and diabetic humans and rodent models suggesting protective effects against renal tubuloglomerular injury. The focus of this review is to present and critically discuss the recent findings on the roles of PPARgamma in the kidney in direct relation to renal function and renal injury in obesity and obesity-initiated diabetes.
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PMID:The complex role of PPARgamma in renal dysfunction in obesity: managing a Janus-faced receptor. 1671 56

Type 2 diabetes mellitus (T2DM) is highly prevalent chronic disease. Recently, many biological targets are discovered for treatment of this disease. The identification of the nuclear hormone receptor peroxisome proliferator activated receptors (PPAR) and their subtypes alpha, gamma and delta or beta as targets for controlling lipid, glucose and energy homeostasis has proved to be exciting. As hyperlipidaemia, obesity and insulin resistance are independent risk factors for coronary heart disease and macrovascular complications of diabetes; new agents that increase insulin sensitivity as well as decrease hyperlipidaemia by distinct yet complementary mechanism are being studied as they may provide improved therapy for T2DM and related disorders. In this article, we review highly potent PPARgamma agonists, PPARalpha/gamma dual agonists, PPAR pan agonists, alternative PPAR ligands like partial agonists or selective PPAR modulators (SPPARMs) and antagonists from a chemist point of view.
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PMID:Fine tuning of PPAR ligands for type 2 diabetes and metabolic syndrome. 1671 31

Lack of adipose tissue, either complete or partial, is the hallmark of disorders known as lipodystrophies. Patients with lipodystrophies suffer from metabolic complications similar to those associated with obesity, including insulin resistance, type 2 diabetes, hypertriglyceridemia, and hepatic steatosis. The loss of body fat in inherited lipodystrophies can be caused by defects in the development and/or differentiation of adipose tissue as a consequence of mutations in a number of genes, including PPARG (encoding a nuclear hormone receptor), AGPAT2 (encoding an enzyme involved in the biosynthesis of triglyceride and phospholipids), AKT2 (encoding a protein involved in insulin signal transduction), and BSCL2 (encoding seipin, whose role in the adipocyte biology remains unclear). The loss of body fat can also be caused by the premature death of adipocytes due to mutations in lamin A/C, nuclear lamina proteins, and ZMPSTE24, which modifies the prelamin A post-translationally. In this review, we focus on the molecular basis of inherited lipodystrophies as they relate to adipocyte biology and their associated phenotypic manifestations.
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PMID:Genetic disorders of adipose tissue development, differentiation, and death. 1672 6

Peroxisome proliferator-activated receptor gamma is a member of the nuclear hormone receptor superfamily. Mainly expressed in adipose tissue, PPARgamma promotes the differentiation of adipocytes and modulates the expression of many genes involved in the synthesis of adipocytokines in the adipose tissue. It is also the target molecule of the thiazolidinediones. Polymorphisms of the PPARgamma gene may influence pancreatic beta-cell function and result in changes in insulin secretion and insulin sensitivity of the peripheral tissues. They are also associated with risks of type 2 diabetes, obesity, cardiovascular diseases and cancer. Elucidation of its mechanism could be of major importance to the diagnosis, prevention and treatment of complex diseases.
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PMID:[PPARgamma variants and complex diseases]. 1687 May 88

Peroxisome proliferator-activated receptor (PPAR) delta is a member of the nuclear hormone receptor superfamily. PPARdelta may ameliorate metabolic diseases such as obesity and diabetes. However, PPARdelta's role in colorectal carcinogenesis remains controversial. Here, we present genetic and pharmacologic evidence demonstrating that deletion of PPARdelta decreases intestinal adenoma growth in Apc(Min/+) mice and inhibits tumor-promoting effects of a PPARdelta agonist GW501516. More importantly, we found that activation of PPARdelta up-regulated VEGF in colon carcinoma cells. VEGF directly promotes colon tumor epithelial cell survival through activation of PI3K-Akt signaling. These results not only highlight concerns about the use of PPARdelta agonists for treatment of metabolic disorders in patients who are at high risk for colorectal cancer, but also support the rationale for developing PPARdelta antagonists for prevention and/or treatment of cancer.
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PMID:Crosstalk between peroxisome proliferator-activated receptor delta and VEGF stimulates cancer progression. 1714 4

Thyroid hormones (THs) have important effects on cellular development, growth, and metabolism. They bind to thyroid hormone receptors (TRs), TRalpha and TRbeta, which belong to the nuclear hormone receptor superfamily. These receptors also bind to enhancer elements in the promoters of target genes, and can regulate both positive and negative transcription. Recent emerging evidence has characterized some of the molecular mechanisms by which THs regulate transcription as co-repressors, and co-activators have been identified and their effects on histone acetylation examined. THs also have rapid effects that do not require transcription. These can occur via TRs or other cellular proteins, and typically occur outside the nucleus. It appears that THs regulate multiple cellular functions using a diverse array of receptors and signaling systems. TR isoform- or pathway-specific drugs might provide the therapeutic benefits of TH action such as decreasing obesity or lowering cholesterol levels without some of the side effects of hyperthyroidism.
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PMID:New insights into thyroid hormone action. 1757 3


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