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)

The recently identified uncoupling protein-3 (UCP-3) gene, predicted to encode a new member of the family of uncoupling proteins, is preferentially expressed in skeletal muscle and has been related to phenotypes of obesity and type 2 diabetes. We have established that during mouse ontogeny, the expression of the UCP-3 gene is switched on in skeletal muscle just after birth. The induction of UCP-3 gene expression is dependent on the initiation of suckling and particularly on lipid intake. Treatment of newborn mice with activators of peroxisome proliferator-activated receptors (PPARs), such as clofibrate, bezafibrate, or (4-chloro-6-(2,3-xylidine)-pirimidinylthio)acetic acid (WY 14,643), mimics the action of food intake on UCP-3 gene expression. The specific ligand of PPAR-alpha WY 14,643 induces UCP-3 gene expression in a time- and dose-dependent manner, whereas the thiazolidinedione BRL 49653, specific for PPAR-gamma, has no effect. These treatments act without altering circulating free fatty acids. During development, skeletal muscle expresses constitutive levels of PPAR-delta mRNA, whereas expression of the PPAR-gamma gene is undetectable. PPAR-alpha gene expression is developmentally regulated in muscle as it is first expressed at birth, just before UCP-3 gene induction occurs. The induction of UCP-3 gene expression by WY 14,643 is impaired in skeletal muscle of premature neonates, which do not express PPAR-alpha. It is proposed that the UCP-3 gene is predominantly regulated in neonatal muscle by PPAR-alpha activation.
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PMID:Activators of peroxisome proliferator-activated receptor-alpha induce the expression of the uncoupling protein-3 gene in skeletal muscle: a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth. 1034 7

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that play an important role in the regulation of genes involved in lipid utilization and storage, lipoprotein metabolism, adipocyte differentiation, and insulin action. The three isoforms of the PPAR family, i.e. alpha, delta, and gamma, have distinct tissue distribution patterns. PPAR-alpha is predominantly present in the liver, and PPAR-gamma in adipose tissue, whereas PPAR-delta is ubiquitously expressed. A recent study reported increased PPAR-gamma messenger RNA (mRNA) expression in the liver in ob/ob mice; however, it is not known whether increased PPAR-gamma expression in the liver has any functional consequences. The expression of PPAR-alpha and -delta in the liver in obesity has not been determined. We have now examined the mRNA levels of PPAR-alpha, -delta, and -gamma in three murine models of obesity, namely, ob/ob (leptin-deficient), db/db (leptin-receptor deficient), and serotonin 5-HT2c receptor (5-HT2cR) mutant mice. 5-HT2cR mutant mice develop a late-onset obesity that is associated with higher plasma leptin levels. Our results show that PPAR-alpha mRNA levels in the liver are increased by 2- to 3-fold in all three obese models, whereas hepatic PPAR-gamma mRNA levels are increased by 7- to 9-fold in ob/ob and db/db mice and by 2-fold in obese 5-HT2cR mutant mice. PPAR-delta mRNA expression is not altered in ob/ob or db/db mice. To determine whether increased PPAR-gamma expression in the liver has any functional consequences, we examined the effect of troglitazone treatment on the hepatic mRNA levels of several PPAR-gamma-responsive adipose tissue-specific genes that have either no detectable or very low basal expression in the liver. The treatment of lean control mice with troglitazone significantly increased the expression of adipocyte fatty acid-binding protein (aP2) and fatty acid translocase (FAT/CD36) in the liver. This troglitazone-induced increase in the expression of aP2 and FAT/CD36 was markedly enhanced in the liver in ob/ob mice. Troglitazone also induced a pronounced increase in the expression of uncoupling protein-2 in the liver in ob/ob mice. In contrast to the liver, troglitazone did not increase the expression of aP2, FAT/CD36, and uncoupling protein-2 in adipose tissue in lean or ob/ob mice. Taken together, our results suggest that the effects of PPAR-gamma activators on lipid metabolism and energy homeostasis in obesity and type 2 diabetes may be partly mediated through their effects on PPAR-gamma in the liver.
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PMID:Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice. 1108 32

In an effort to understand the role of key eicosanoid-forming enzymes in the activation of peroxisome proliferator-activated receptor (PPAR), this study was designed to evaluate the possible contributions of cytosolic phospholipase A(2) (cPLA(2)) and group IIA secretory phospholipase A(2) (sPLA(2)) in the regulation of PPAR-mediated gene transcription in a human hepatoma cell line (HepG2). The HepG2 cells express both PPAR-alpha and -gamma but not PPAR-beta. Overexpression of cPLA(2), but not group IIA sPLA(2) in the HepG2 cells, caused a significantly increased PPAR-alpha/gamma-mediated reporter activity. Antisense inhibition of cPLA(2) resulted in a significantly decreased PPAR-alpha/gamma activity. The PPAR-alpha/gamma-induced gene transcription in the HepG2 cells was inhibited by the cPLA(2) inhibitors methyl arachidonyl fluorophosphonate and arachidonyltrifluoromethyl ketone, but not by the sPLA(2) inhibitor LY311727. The expression of PPAR-alpha-mediated endogenous gene apolipoprotein A-II was increased in cells with overexpression of cPLA(2), decreased in cells with antisense inhibition of cPLA(2), but unaltered in cells with overexpression of group IIA sPLA(2). The above results demonstrated an important role of cPLA(2), but not group IIA sPLA(2) in the control of PPAR activation. The cPLA(2)-mediated PPAR activation was likely mediated by arachidonic acid and prostaglandin E(2). This study reveals a novel intracellular function of cPLA(2) in PPAR activation in HepG2 cells. The cPLA(2) thus may represent a potential therapeutic target for the control of PPAR-related liver and metabolic disorders such as obesity, lipid metabolic disorders, diabetes mellitus, and atherosclerosis.
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PMID:85-kDa cPLA(2) plays a critical role in PPAR-mediated gene transcription in human hepatoma cells. 1189 17

Nonalcoholic steatohepatitis, often associated with obesity and diabetes, is a common liver condition in the U.S. Individuals with steatohepatitis are not eligible for liver donation and may be at increased risk from developing complications following lobectomy. If steatosis and steatohepatitis can be treated medically, these individuals can become eligible for living donor transplants and segmental resection of the liver for treatment of primary or metastatic liver diseases. Because rats fed a choline-deficient diet (CDD) develop morphological changes in the liver similar to that observed in nonalcoholic steatohepatitis, we examined the effect of ciprofibrate, a potent peroxisome proliferator activated receptor alpha (PPAR alpha) ligand and inducer of fatty acid oxidation systems in the liver, on reversal of steatosis. Rats fed CDD for 2 weeks developed marked fatty change with mild hepatitis and marked increase in serum aminotransferases and liver triacylglycerols. Concurrent administration of CDD and ciprofibrate resulted in the prevention of fatty change. Rats that were fed CDD for 2 weeks followed by feeding CDD containing ciprofibrate for 1 or 2 weeks resulted in marked reduction of fatty change and normalization of serum aminotransferases. Compared with the CDD group, all groups that received ciprofibrate showed several-fold increase in mRNA and protein levels of several PPAR alpha target genes. In addition, electron microscopic examination showed marked peroxisome proliferation in the hepatocytes. The results of these studies clearly demonstrate that the severity of CDD-induced fatty change and hepatitis in rats can be rapidly decreased by ciprofibrate and suggest the therapeutic potential of PPAR alpha ligands in the treatment of nonalcoholic steatohepatitis in humans to rapidly reverse liver changes.
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PMID:Prevention/reversal of choline deficiency-induced steatohepatitis by a peroxisome proliferator-activated receptor alpha ligand in rats. 1207 74

Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.
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PMID:Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. 1280 37

Substituted phenylpropanoic acid derivatives were prepared as part of a search for subtype-selective human peroxisome proliferator activated receptor alpha (PPARalpha) activators. Structure-activity relationship studies indicated that the nature and the stereochemistry of the substituent at the alpha-position of the head part containing the carboxyl group, the distance between the carboxyl group and the central benzene ring, the linking group between the central benzene ring and the distal benzene ring, and the substituent at the distal hydrophobic tail part of the molecule all play key roles in determining the potency and selectivity of PPAR subtype transactivation. This study has led to the identification of potent and human PPARalpha selective optically active alpha-alkylphenylpropanoic acid derivatives, which will be useful not only as pharmacological tools to investigate the physiology and pathophysiology of PPARalpha but also as candidate drugs for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.
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PMID:Design, synthesis, and evaluation of substituted phenylpropanoic acid derivatives as human peroxisome proliferator activated receptor activators. Discovery of potent and human peroxisome proliferator activated receptor alpha subtype-selective activators. 1290 63

Alterations in hepatic glucose metabolism play a key role in the development of the hyperglycemia observed in type 2 diabetes. Because the transcription factor c-Myc induces hepatic glucose uptake and utilization and blocks gluconeogenesis, we examined whether hepatic overexpression of c-myc counteracts the insulin resistance induced by a high-fat diet. After 3 months on this diet, control mice became obese, hyperglycemic, and hyperinsulinemic, indicating that they had developed insulin resistance. In contrast, transgenic mice remained lean and showed improved glucose disposal and normal levels of blood glucose and insulin, indicating that they had developed neither obesity nor insulin resistance. These findings were concomitant with normalization of hepatic glucokinase and pyruvate kinase gene expression and enzyme activity, which led to normalization of intrahepatic glucose-6-phosphate and glycogen content. In the liver of control mice fed a high-fat diet, the expression of genes encoding proteins that control energy metabolism, such as sterol receptor element binding protein 1-c, peroxisome proliferator activated receptor alpha, and uncoupling protein-2, was altered. In contrast, in the liver of transgenic mice fed a high-fat diet, the expression of these genes was normal. These results suggest that c-myc overexpression counteracted the obesity and insulin resistance induced by a high-fat diet by modulating the expression of genes that regulate hepatic metabolism.
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PMID:Overexpression of c-myc in the liver prevents obesity and insulin resistance. 1295 86

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 receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. Three different PPARs, PPAR-alpha, -gamma, and -delta, have been characterized, and they are distinguished from each other by tissue distribution and cell activation. All PPARs are, to different extents, activated by fatty acids and derivatives. Recently, it has been shown that PPAR-delta serves as a widespread regulator of fat burning, suggesting that it might be a potential target in the treatment of obesity and type 2 diabetes. In an effort to identify polymorphic markers in potential candidate genes for type 2 diabetes, we have sequenced PPAR-delta, including -1,500 bp of the 5' flanking region. Nine polymorphisms were identified in PPAR-delta: four in the intron, one in the 5' untranslated region (UTR), and four in the 3' UTR. Among identified polymorphisms, five common sites, including c.-13454G>T, c.-87T>C, c.2022+12G>A, c.2629T>C, and c.2806C>G, were genotyped in subjects with type 2 diabetes and normal control subjects (n = 702). The genetic associations with the risk of type 2 diabetes and metabolic phenotype were analyzed. No significant associations with the risk of type 2 diabetes were detected. However, several positive associations of PPAR-delta polymorphisms with fasting plasma glucose and BMI were detected in nondiabetic control subjects. The genetic information about PPAR-delta from this study would be useful for further genetic study of obesity, diabetes, and other metabolic diseases.
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PMID:Genetic polymorphisms in peroxisome proliferator-activated receptor delta associated with obesity. 1498 73

Obesity and the related disorders of dyslipidemia and diabetes (components of syndrome X) have become global health epidemics. Over the past decade, the elucidation of key regulators of energy balance and insulin signaling have revolutionized our understanding of fat and sugar metabolism and their intimate link. The three 'lipid-sensing' peroxisome proliferator-activated receptors (PPAR-alpha, PPAR-gamma and PPAR-delta) exemplify this connection, regulating diverse aspects of lipid and glucose homeostasis, and serving as bona fide therapeutic targets. With molecular underpinnings now in place, new pharmacologic approaches to metabolic disease and new questions are emerging.
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PMID:PPARs and the complex journey to obesity. 1505 33


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