Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity-associated diabetes is epidemic in industrialized societies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and the presumed molecular target for antidiabetic thiazolidinedione drugs that reverse insulin resistance but also promote weight gain. Phosphorylation reduces the activity of PPARgamma in vitro, but physiological relevance has not been demonstrated. We have studied mice homozygous for a mutation (S112A) that prevents PPARgamma phosphorylation. Surprisingly, the weights and adipose mass of PPARgamma-S112A mice are not greater than wild-type. Remarkably, however, genetic prevention of PPARgamma phosphorylation preserves insulin sensitivity in the setting of diet-induced obesity. Underlying this protection are smaller fat cells, elevated serum adiponectin, and reduced free fatty acid levels. Thus, the phosphorylation state of PPARgamma modulates insulin sensitivity. Compounds that prevent PPARgamma phosphorylation or ligands that induce the conformation of nonphosphorylated PPARgamma may selectively enhance insulin sensitivity without increasing body weight.
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PMID:Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity. 1453 66

Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the ligand-activated nuclear receptor superfamily, plays a key role in mediating differentiation of adipocytes and regulating fat metabolism. PPARgamma has been implicated in the pathophysiology of atherosclerosis, inflammation, obesity, diabetes, immune response, and ageing. Recently, it has been shown that activation of PPARgamma by J(2) series cyclopentenone prostaglandins (cyPGs), especially 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) or synthetic agents, such as antidiabetic thiazolidinediones, causes anti-proliferation, apoptosis, differentiation, and anti-inflammation of certain types of cancer cells. The anti-proliferative effects of PPARgamma activators are associated with de novo synthesis of proteins involved in regulating the cell cycle and cell survival/death. Anti-inflammatory effects of 15d-PGJ(2) are associated with interruption of nuclear factor-kappaB and subsequent blockade of inflammatory gene expression. Furthermore, 15d-PGJ(2) at nontoxic doses induce expression of phase II detoxification or stress-responding enzymes, which may confer cellular resistance or adaptation to oxidative stress. The presence of a reactive alpha,beta-unsaturated carbonyl moiety in the cyclopentenone ring of 15d-PGJ(2) is important for part of biological functions this cyPG has. Recently, attention has been focused on the anti-proliferative activity of nonsteroidal anti-inflammatory drugs (NSAIDs) in cancerous or transformed cells, which is mediated through interaction with PPARgamma irrespective of their ability to inhibit COX-2. Despite the fact that abnormally elevated COX-2 is associated with resistance to cell death, induction of apoptosis by certain NSAIDs is accompanied by up-regulation of COX-2 expression. This commentary focuses on dual effects of the typical PPARgamma agonist 15d-PGJ(2) on cell proliferation and growth, and its possible involvement in the NSAID-induced COX-2 expression and apoptosis.
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PMID:Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands as bifunctional regulators of cell proliferation. 1455 12

The estrogen-related receptor alpha (ERRalpha) is an orphan member of the superfamily of nuclear hormone receptors expressed in tissues that preferentially metabolize fatty acids. Despite the molecular characterization of ERRalpha and identification of target genes, determination of its physiological function has been hampered by the lack of a natural ligand. To further understand the in vivo function of ERRalpha, we generated and analyzed Estrra-null (ERRalpha-/-) mutant mice. Here we show that ERRalpha-/- mice are viable, fertile and display no gross anatomical alterations, with the exception of reduced body weight and peripheral fat deposits. No significant changes in food consumption and energy expenditure or serum biochemistry parameters were observed in the mutant animals. However, the mutant animals are resistant to a high-fat diet-induced obesity. Importantly, DNA microarray analysis of gene expression in adipose tissue demonstrates altered regulation of several enzymes involved in lipid, eicosanoid, and steroid synthesis, suggesting that the loss of ERRalpha might interfere with other nuclear receptor signaling pathways. In addition, the microarray study shows alteration in the expression of genes regulating adipogenesis as well as energy metabolism. In agreement with these findings, metabolic studies showed reduced lipogenesis in adipose tissues. This study suggests that ERRalpha functions as a metabolic regulator and that the ERRalpha-/- mice provide a novel model for the investigation of metabolic regulation by nuclear receptors.
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PMID:Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. 1458 56

Current lipid-altering agents that lower low density lipoprotein cholesterol (LDL-C) primarily through increased hepatic LDL receptor activity include statins, bile acid sequestrants/resins and cholesterol absorption inhibitors such as ezetimibe, plant stanols/sterols, polyphenols, as well as nutraceuticals such as oat bran, psyllium and soy proteins; those currently in development include newer statins, phytostanol analogues, squalene synthase inhibitors, bile acid transport inhibitors and SREBP cleavage-activating protein (SCAP) activating ligands. Other current agents that affect lipid metabolism include nicotinic acid (niacin), acipimox, high-dose fish oils, antioxidants and policosanol, whilst those in development include microsomal triglyceride transfer protein (MTP) inhibitors, acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, gemcabene, lifibrol, pantothenic acid analogues, nicotinic acid-receptor agonists, anti-inflammatory agents (such as Lp-PLA(2) antagonists and AGI1067) and functional oils. Current agents that affect nuclear receptors include PPAR-alpha and -gamma agonists, while in development are newer PPAR-alpha, -gamma and -delta agonists, as well as dual PPAR-alpha/gamma and 'pan' PPAR-alpha/gamma/delta agonists. Liver X receptor (LXR), farnesoid X receptor (FXR) and sterol-regulatory element binding protein (SREBP) are also nuclear receptor targets of investigational agents. Agents in development also may affect high density lipoprotein cholesterol (HDL-C) blood levels or flux and include cholesteryl ester transfer protein (CETP) inhibitors (such as torcetrapib), CETP vaccines, various HDL 'therapies' and upregulators of ATP-binding cassette transporter (ABC) A1, lecithin cholesterol acyltransferase (LCAT) and scavenger receptor class B Type 1 (SRB1), as well as synthetic apolipoprotein (Apo)E-related peptides. Fixed-dose combination lipid-altering drugs are currently available such as extended-release niacin/lovastatin, whilst atorvastatin/amlodipine, ezetimibe/simvastatin, atorvastatin/CETP inhibitor, statin/PPAR agonist, extended-release niacin/simvastatin and pravastatin/aspirin are under development. Finally, current and future lipid-altering drugs may include anti-obesity agents which could favourably affect lipid levels.
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PMID:Pharmacotherapy for dyslipidaemia--current therapies and future agents. 1459 46

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor transcription factor that regulates cell growth, differentiation, and homeostasis. PPARgamma agonists are potent therapeutic agents for type 2 diabetes, obesity, and inflammation. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis. We have shown recently that PPARgamma agonists inhibit EAE by blocking IL-12 production, IL-12 signaling, and neural Ag-induced Th1 differentiation. In this study, we show that the PPARgamma-deficient heterozygous mice develop an exacerbated EAE with prolonged clinical symptoms than the wild-type littermates, following immunization with myelin oligodendrocyte glycoprotein (MOG) p35-55 peptide. The exacerbation of EAE in PPARgamma(+/-) mice associates with an increased expansion of CD4(+) and CD8(+) T cells and expression of CD40 and MHC class II molecules in response to MOGp35-55 Ag. The PPARgamma(+/-) mice also showed an increase in T cell proliferation and Th1 response to MOGp35-55 Ag than the wild-type littermates. These findings suggest that PPARgamma be a critical physiological regulator of CNS inflammation and demyelination in EAE and perhaps multiple sclerosis and other Th1 cell-mediated autoimmune diseases.
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PMID:Peroxisome proliferator-activated receptor-gamma-deficient heterozygous mice develop an exacerbated neural antigen-induced Th1 response and experimental allergic encephalomyelitis. 1463 82

PPARdelta (peroxisome proliferator-activated receptor delta)-specific agonists decrease plasma lipids and insulinaemia in obese animals. As skeletal muscle is one of the major organs for fatty acid catabolism, we have investigated the roles of the nuclear receptor in the control of muscle development and lipid metabolism, by using two approaches. We have used C(2)C(12) myotubes in which the PPARdelta activity was altered by overexpression of either native or dominant-negative (DN) mutant forms of PPARdelta. Treatment of C(2)C(12) cells by specific PPARdelta agonists promotes expression of genes for proteins of fatty acid catabolism and increases fatty acid oxidation. These responses were increased in C(2)C(12)-PPARdelta cells and impaired in C(2)C(12)-PPARdeltaDN cells. We also constructed animal models with muscle-specific expression of PPARdelta (Cre/Lox approach). The effects of muscle-specific alteration of PPARdelta activity were studied on muscle development and metabolism as well as on body fat mass. These experiments indicated that PPARdelta plays a crucial role in myofibre typing determination and regulation of muscle oxidative capabilities, and that muscle-specific overexpression of the nuclear receptor leads to reduction of adipocyte size and body fat mass. These data strongly suggest that PPARdelta controls fatty acid catabolism in muscle and that its activation by synthetic agonists could prevent or correct obesity and type 2 diabetes.
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PMID:Roles of PPARdelta in the control of muscle development and metabolism. 1464 Oct 10

The metabolic function of the nuclear receptor peroxisome proliferator-activated receptor delta (PPAR(delta)) has been established by transfer of the PPAR(delta) gene into adipose tissue of mice in vivo and into adipocytes in culture. Investigators found that PPAR(delta) activation by such transfer leads to up-regulation of energy expenditure by fatty acid oxidation. PPAR(delta) activation also results in lowered serum triglyceride and free fatty acid levels and decreased lipid accumulation. In vivo activation of PPAR(delta) in adipose tissue protects against obesity and fatty liver in mice fed a high-calorie diet. PPAR(delta) also activates the heat-producing uncoupling enzymes in brown adipose tissue (UCP1 and 3) and muscle (UCP2).
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PMID:The function of the nuclear receptor peroxisome proliferator-activated receptor delta in energy homeostasis. 1467 74

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor isoforms with key roles in the regulation of lipid and glucose metabolism. Synthetic ligands for PPAR gamma (and PPAR alpha) have effects of promoting insulin sensitization in the context of obesity. Recent evidence suggests that activation of PPAR delta might produce similar effects. Both PPAR gamma and PPAR alpha have also been shown to produce selected anti-inflammatory effects and to reduce the progression of atherosclerosis in animals (alpha and gamma) or in humans (alpha). Mechanisms underlying insulin-sensitizing effects are complex. For PPAR gamma, direct effects on adipose tissue lipid metabolism with secondary benefits in liver and/or muscle (lipid levels and insulin signaling) have been implicated. For PPAR alpha, accelerated lipid catabolism may contribute to reduced muscle or liver 'steatosis'. Anti-inflammatory mechanisms as contributors to the beneficial metabolic effects of PPAR activation are also worth considering for the following reasons: (1) obesity and insulin resistance are associated with a proinflammatory milieu. (2) PPAR gamma has clear effects to oppose the effects of tumor necrosis factor-alpha (TNFalpha) in adipocytes. (3) effects of PPAR ligands on cytokine-mediated signaling (eg via NF-kappa B) may be expected to enhance insulin action. (4) Adipose production of several molecules that are implicated as markers or mediators of inflammation is reduced. (5) In humans, treatment with either PPAR alpha or PPAR gamma agonists has been shown to reduce circulating levels of proteins that serve as markers of inflammation. (6) Adiponectin, a fat-derived circulating factor that has been implicated as having anti-inflammatory activity, is induced by PPAR gamma agonism.
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PMID:Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. 1470 38

Insulin resistance is a key metabolic defect in type 2 diabetes that is exacerbated by obesity, especially if the excess adiposity is located intra-abdominally/centrally. Insulin resistance underpins many metabolic abnormalities-collectively known as the insulin resistance syndrome-that accelerate the development of cardiovascular disease. Thiazolidinedione anti-diabetic agents improve glycaemic control by activating the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma). This receptor is highly expressed in adipose tissues. In insulin resistant fat depots, thiazolidinediones increase pre-adipocyte differentiation and oppose the actions of pro-inflammatory cytokines such as tumour necrosis factor-alpha. The metabolic consequences are enhanced insulin signalling, resulting in increased glucose uptake and lipid storage coupled with reduced release of free fatty acids (FFA) into the circulation. Metabolic effects of PPARgamma activation are depot specific-in people with type 2 diabetes central fat mass is reduced and subcutaneous depots are increased. Thiazolidinediones increase insulin sensitivity in liver and skeletal muscle as well as in fat, but they do not express high levels of PPARgamma, suggesting that improvement in insulin action is indirect. Reduced FFA availability from adipose tissues to liver and skeletal muscle is a pivotal component of the insulin-sensitising mechanism in these latter two tissues. Adipocytes secrete multiple proteins that may both regulate insulin signalling and impact on abnormalities of the insulin resistance syndrome--this may explain the link between central obesity and cardiovascular disease. Of these proteins, low plasma adiponectin is associated with insulin resistance and atherosclerosis--thiazolidinediones increase adipocyte adiponectin production. Like FFA, adiponectin is probably an important signalling molecule regulating insulin sensitivity in muscle and liver. Adipocyte production of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, and angiotensin II secretion are partially corrected by PPARgamma activation. The favourable modification of adipocyte-derived cardiovascular risk factors by thiazolidinediones suggests that these agents may reduce cardiovascular disease as well as provide durable glycaemic control in type 2 diabetes.
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PMID:Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones. 1473 74

The orphan nuclear receptor CAR (NR1I3) has been characterized as a central component in the coordinate response to xenobiotic and endobiotic stress. In this study, we demonstrate that CAR plays a pivotal function in energy homeostasis and establish an unanticipated metabolic role for this nuclear receptor. Wild-type mice treated with the synthetic CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) exhibited decreased serum concentration of the thyroid hormone (TH) thyroxine (T(4)). However, treatment of Car(-/-) mice with TCPOBOP failed to elicit these changes. To examine whether CAR played a role in the regulation of TH levels under physiological conditions, wild-type and Car(-/-) mice were fasted for 24 h, a process known to alter TH metabolism in mammals. As expected, the serum triiodothyronine and T(4) concentrations decreased in wild-type mice. However, triiodothyronine and T(4) levels in fasted Car(-/-) mice remained significantly higher than those in fasted wild-type animals. Concomitant with the changes in serum TH levels, both CAR agonist treatment and fasting induced the expression of CAR target genes (notably, Cyp2b10, Ugt1a1, Sultn, Sult1a1, and Sult2a1) in a receptor-dependent manner. Importantly, the Ugt1a1, Sultn, Sult1a1, and Sult2a1 genes encode enzymes that are capable of metabolizing TH. An attenuated reduction in TH levels during fasting, as observed in Car(-/-) mice, would be predicted to increase weight loss during caloric restriction. Indeed, when Car(-/-) animals were placed on a 40% caloric restriction diet for 12 weeks, Car(-/-) animals lost over twice as much weight as their wild-type littermates. Thus, CAR participates in the molecular mechanisms contributing to homeostatic resistance to weight loss. These data imply that CAR represents a novel therapeutic target to uncouple metabolic rate from food intake and has implications in obesity and its associated disorders.
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PMID:The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. 1500 31


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