Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To explore the possibility that raloxifene might influence an adipocyte differentiation and lipogenesis, we studied the effects of raloxifene on the expression of adiponectin and other peroxisome proliferator-activated receptor gamma targeting genes using the 3T3-L1 adipocytes. With standard adipogenic inducers, we added raloxifene at various doses for the adipocyte differentiation. Higher doses of raloxifene facilitated lipid accumulation of the 3T3-L1 cells. We next examined the differentiating and differentiated adipocytes and found that raloxifene augmented mRNA levels of adiponectin, adipocyte-specific fatty acid binding protein, and lipoprotein lipase dose-dependently in both. These effects were opposite those of 17beta-estradiol treatment. These findings suggest that raloxifene promotes adipocyte differentiation, providing a novel insight into the treatment of postmenopausal metabolic syndrome with hypoadiponectinemia.
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PMID:Raloxifene promotes adipocyte differentiation of 3T3-L1 cells. 1664 90

Over the last two decades, the incidence of obesity and associated metabolic syndrome diseases has risen dramatically, becoming a global health crisis. Increased caloric intake and decreased physical activity are believed to represent the root causes of this dramatic rise. However, recent findings highlight the possible involvement of environmental obesogens, xenobiotic chemicals that can disrupt the normal developmental and homeostatic controls over adipogenesis and energy balance. Environmental estrogens, i.e. chemicals with estrogenic potential, have been reported to perturb adipogenic mechanisms using in vitro model systems, but other classes of endocrine-disrupting chemicals are now coming under scrutiny as well. Organotins represent one class of widespread persistent organic pollutants with potent endocrine-disrupting properties in both invertebrates and vertebrates. New data identify tributyltin chloride and triphenyltin chloride as nanomolar agonist ligands for retinoid X receptor (RXR alpha, RXR beta, and RXR gamma) and peroxisome proliferator-activated receptor gamma, nuclear receptors that play pivotal roles in lipid homeostasis and adipogenesis. The environmental obesogen hypothesis predicts that inappropriate receptor activation by organotins will lead directly to adipocyte differentiation and a predisposition to obesity and/or will sensitize exposed individuals to obesity and related metabolic disorders under the influence of the typical high-calorie, high-fat Western diet. The linking of organotin exposure to adipocyte differentiation and obesity opens an important new area of research into potential environmental influences on human health and disease.
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PMID:Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling. 1669 Aug 1

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

Diabetes mellitus (DM) is considered a major public health problem in both developed and developing countries due to its chronic complications, at the macro or microcirculation, with great impact on mortality and morbidity in all patients. The disease is considered the end of a pathophysiologic process involving peripheral and hepatic insulin resistance and reduced insulin secretion that have been started years before the clinical diagnosis. Metabolic syndrome (MS) is a disorder that results from the increasing prevalence of obesity worldwide. DM is frequently associated with clinical and laboratory features of MS, like abdominal obesity, hypertension, dyslipidemia and microalbuminuria that are also risk factors for cardiovascular disease. Populational studies have demonstrated increasing prevalence of all the features of MS from pre-diabetes to clinical DM resulting in a great risk of cardiovascular disease. The prevalence of MS in DM type 2 is estimated to be >80%. Glitazones are PPAR-gamma agonists that improve insulin sensitivity. These drugs induce the transcription of genes related to glucose and lipid metabolism, and expression of inflammatory and endothelial proteins associated with atherosclerosis process resulting in an improvement in endothelial function. However several questions need to be clarified regarding the glitazones, in special those associated with their adverse effects such as weight gain, edema and heart failure.
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PMID:[Glitazones and the metabolic syndrome: mechanism of action, pathophysiology and therapeutic indications]. 1676 93

Metabolic syndrome and type 2 diabetes mellitus are associated with an increased number of macrophage cells that infiltrate white adipose tissue (WAT). Previously, we demonstrated that the treatment of subjects with impaired glucose tolerance (IGT) with the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone resulted in a decrease in macrophage number in adipose tissue. Here, adipose tissue samples from IGT subjects treated with pioglitazone were examined for apoptosis with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. TUNEL-positive cells were identified, and there was a significant 42% increase in TUNEL-positive cells following pioglitazone treatment. Overlay experiments with anti-CD68 antibody demonstrated that most of the TUNEL-positive cells were macrophages. To determine whether macrophage apoptosis was a direct or indirect effect of pioglitazone treatment, human THP1 cells were treated with pioglitazone in vitro, demonstrating increased TUNEL staining in a dose- and time-dependent manner. Furthermore, the appearance of the active proteolytic subunits of caspase-3 and caspase-9 were detected in cell lysate from THP1 cells and also increased in a dose- and time-dependent manner following pioglitazone treatment. Pretreatment with a PPARgamma inhibitor, GW9662, prevented pioglitazone induction of the apoptotic pathway in THP1 cells. Differentiated human adipocytes did not show any significant increase in apoptosis after treatment in vitro with piolgitazone. These findings indicate that PPARgamma has distinct functions in different cell types in WAT, such that pioglitazone reduces macrophage infiltration by inducing apoptotic cell death specifically in macrophages through PPARgamma activation.
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PMID:Pioglitazone induces apoptosis of macrophages in human adipose tissue. 1679 31

The discovery of the peroxisome proliferator-activated receptors (PPARs) in 1990s provided new insights in understanding the mechanisms involved in the control of energy homeostasis and in cell differentiation, proliferation, apoptosis and the inflammatory process. The PPARs became thus an exciting therapeutic target for diabetes, metabolic syndrome, atherosclerosis, and cancer. Unexpectedly, genetic studies performed in mice established that PPARgamma are essential for placental development. After a brief description of structural and functional features of PPARs, we will summarize in this review the most recent results concerning expression and the role of PPARs in placenta and of PPARgamma in human trophoblastic cells in particular.
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PMID:PPARs and the placenta. 1683 93

Hypertension is a cardiovascular risk factor commonly associated with insulin resistance, the metabolic syndrome, and type 2 diabetes mellitus. Recent in vitro data indicate that certain angiotensin receptor antagonists, for example, telmisartan, activate peroxisome proliferator-activated receptor gamma (PPAR-gamma) and increase adiponectin protein content in adipocytes. By this means, they may improve insulin sensitivity in vivo. To investigate the effect of antihypertensive treatment on insulin sensitivity and fasting adiponectin serum levels, 37 nondiabetic patients with essential hypertension were randomized to receive telmisartan, the calcium channel blocker nisoldipine, or their combination for 6 weeks in a prospective, parallel group study. Fasting serum glucose, insulin, and adiponectin were evaluated before, 3 weeks (low dose), and 6 weeks (high dose) after initiation of treatment. Furthermore, the effect of telmisartan on PPAR-gamma receptor activity was investigated in vitro using a PPAR-gamma reporter gene assay. As reported previously, telmisartan significantly enhanced PPAR-gamma receptor activity in vitro. At baseline, a positive correlation between insulin serum levels and body mass index of investigated subjects was observed, whereas body mass index and serum adiponectin levels were negatively associated. High-dose treatment with telmisartan but not with nisoldipine reduced serum insulin levels as well as the homeostasis model assessment of insulin resistance, but did not affect serum adiponectin levels. In conclusion, in our study cohort of nondiabetic patients with essential hypertension, telmisartan improved insulin sensitivity by mechanisms apparently not involving adiponectin induction. Future studies will demonstrate whether these telmisartan-induced effects may contribute to a blood pressure-independent reduction in cardiovascular morbidity.
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PMID:Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension. 1691 33

The discovery of the crucial role of peroxisome proliferator-activated receptors (PPARs) as regulators of lipid and glucose metabolism has raised interest in the development of synthetic ligands as potential tools for therapeutic intervention in type 2 diabetes and the metabolic syndrome. PPARalpha activators primarily improve dyslipidemia, whereas thiazolidinediones are potent PPARgamma activators that improve insulin resistance. Important research programs to develop agonists that combine the therapeutic effects of both PPARalpha- and PPARgamma-selective agonists, creating the expectation of greater efficacy and other advantages in the treatment of type 2 diabetes and the metabolic syndrome, have therefore been undertaken. Among these dual PPARalpha/gamma agonists, compounds that belong to the glitazar class are in the most advanced stage of development. However, although they demonstrated beneficial impact over selective PPAR agonists by improving both lipid and glucose homeostasis, safety has been a critical issue and has led to the discontinuation of their development because of adverse toxicity profiles. However, the target-related mechanism responsible for the identified safety issues and the relevance of rodent toxicities to the human situation are unclear. Therefore, future development of dual PPARalpha/gamma agonists with selective PPAR modulator activity appears appropriate and should be feasible.
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PMID:PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome. 1697 18

The mouse lipin gene, Lpin1, is important for adipose tissue development and is a candidate gene for insulin resistance. Here, we investigate the adipose tissue expression levels of the human LPIN1 gene in relation to various clinical variables as well as adipocyte function. LPIN1 gene expression was induced at an early step in human preadipocyte differentiation in parallel with peroxisome proliferator-activated receptor gamma. Lipin mRNA levels were higher in fat cells than in adipose tissue segments but showed no difference between subcutaneous and omental depots. Moreover, LPIN1 expression levels were reduced in obesity, improved following weight reduction in obese subjects, and were downregulated in women with the metabolic syndrome. With respect to adipocyte function, adipose LPIN1 gene expression was strongly associated with both basal and insulin-mediated subcutaneous adipocyte glucose transport as well as mRNA levels of glucose transporter 4 (GLUT4). We show that body fat accumulation is a major regulator of human adipose LPIN1 expression and suggest a role of LPIN1 in human preadipocyte as well as mature adipocyte function.
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PMID:A role of lipin in human obesity and insulin resistance: relation to adipocyte glucose transport and GLUT4 expression. 1703 74


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