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)

PPARs are transcription factors belonging to the super family of hormonal receptors. Their activity is regulated by fibrates, thiazolidinediones, certain anti inflammatory drugs and fatty acid derivatives, present in food. PPAR isoforms play a central role in lipid homeostasis, regulating anabolic (PPAR gamma) and catabolic (PPAR alpha) pathways of lipid metabolism. Additionally, these receptors participate in glucose homeostasis, influence cellular proliferation and differentiation and participate in inflammatory processes. The effects of PPARs on oxidative substrate partitioning suggests that they have a relevant role in the development of obesity and insulin resistance.
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PMID:[Molecular nutrition, role of the PPAR system in lipidic metabolism and its importance in obesity and diabetes mellitus]. 1096 63

The Pro(12)Ala (P12A) variant of exon B of the peroxisome proliferator-activated receptor gamma(2) (PPAR gamma) been variably associated with obesity, insulin sensitivity, diabetes, and dyslipidemia, but its role in insulin resistance-associated traits remains uncertain. We tested the hypothesis that this variant is associated with the insulin resistance syndrome by genotyping 619 members of 52 familial type 2 diabetes kindreds. A subset of 124 family members underwent iv glucose tolerance tests and minimal model determination of insulin sensitivity. We estimated the frequency of the A12 allele as 0.12, within the range observed in random Caucasian samples. We were unable to demonstrate any effect on direct measures of insulin sensitivity, and no trait was linked to markers near PPAR gamma on chromosome 3q. However, body mass index, serum total cholesterol levels, triglyceride levels, systolic and diastolic blood pressures, and glucose concentration showed at least a trend to association (P < 0.1) when tested separately for a family-based association. When these 6 traits were included in a multivariate analysis, body mass index, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration remained significantly associated with the P12A variant (P < 0.05), whereas the effect of P12A on liability for diabetes was not significant. The predicted means for each trait and each genotype suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals who comprise only 1--2% of the population. We confirm an association of the P12A variant in traits commonly ascribed to the insulin resistance syndrome, but not with direct measures of insulin sensitivity. The tendency for this variant to act in a recessive manner with effects on multiple traits may explain the inconsistent associations noted in previous studies.
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PMID:Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds. 1115 5

The peroxisome proliferator-activated receptors (PPARalpha, gamma, delta) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have central roles in the storage and catabolism of fatty acids. Although the three PPAR subtypes are closely related and bind to similar DNA response elements as heterodimers with the 9-cis retinoic acid receptor RXR, each subserves a distinct physiology. PPARalpha (NR1C1) is the receptor for the fibrate drugs, which are widely used to lower triglycerides and raise high-density lipoprotein cholesterol levels in the treatment and prevention of coronary artery disease. In rodents, PPARalpha agonists induce hepatomegaly and stimulate a dramatic proliferation of peroxisomes as part of a coordinated physiological response to lipid overload. PPARgamma (NR1C3) plays a critical role in adipocyte differentiation and serves as the receptor for the glitazone class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. In contrast to PPARalpha and PPARgamma, relatively little is known about the biology of PPARdelta (NR1C2), although recent findings suggest that this subtype also has a role in lipid homeostasis. All three PPARs are activated by naturally occurring fatty acids and fatty acid metabolites, indicating that they function as the body's fatty acid sensors. Three-dimensional crystal structures reveal that the ligand-binding pockets of the PPARs are much larger and more accessible than those of other nuclear receptors, providing a molecular basis for the promiscuous ligand-binding properties of these receptors. Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are likely to be useful for treating a wide range of metabolic disorders, including atherosclerosis, dyslipidemia, obesity, and type 2 diabetes.
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PMID:Peroxisome proliferator-activated receptors: from genes to physiology. 1123 16

The nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) is a transcription factor that is activated by polyunsaturated fatty acids and their metabolites and is essential for fat cell formation. Although obesity is a strong risk factor for type 2 diabetes mellitus and other metabolic diseases, potent PPAR gamma activators such as the glitazone drugs lower glucose and lipid levels in patients with type 2 diabetes and also have antiatherosclerotic and antihypertensive effects. We review recent studies providing insight into the paradoxical relationship between PPAR gamma and metabolic disease. We also review recent advances in understanding the structural basis for PPAR gamma activation by ligands. The unusual ligand-binding properties of PPAR gamma suggest that it will be possible to discover new chemical classes of receptor "modulators" with distinct pharmacological activities for the treatment of type 2 diabetes and other metabolic diseases.
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PMID:Peroxisome proliferator-activated receptor gamma and metabolic disease. 1139 11

Since evidence has appeared that alpha and gamma isoforms of the peroxisome proliferator receptors (PPARs) are involved in the regulation of triglyceride homeostasis and in the control of the differentiation of adipocytes that is required for the development of obesity, a large number of studies have investigated the physiologic role of nuclear receptors in the control of energy balance. The aim of this study was to determine the early effects of an obesity-inducing diet on the expression of PPAR alpha and gamma and other nuclear receptors such as all-trans retinoic acid receptor (RAR) and triiodothyronine receptor (TR), which all form functional heterodimers with a common partner, the 9-cis retinoic acid receptor (RXR). The experiment used a cafeteria diet where 60% of the energy was supplied as lipids. This diet was offered to young rats for 8 and 28 days and the expression of nuclear receptors was determined at the end of each experimental time period (1) in the liver by assaying the binding properties of RAR and TR and by quantifying mRNA levels of RAR beta, TR alpha(1)beta(1), RXR alpha, and PPAR alpha, and (2) in the white adipose tissue (WAT) by quantifying mRNA levels of RAR alpha, RXR alpha, TR alpha(1)beta(1), and PPAR gamma(2). After 8 days of cafeteria diet a significant decrease of RAR and TR maximal binding capacity (MBC) was observed in the liver (-20.1% and -35.0%, respectively, P <.05) and the level of the mRNA of RAR beta was significantly decreased (-17.4%, P <.05). After 28 days of cafeteria diet, the level of the mRNA of PPAR alpha and acyl-CoA oxidase (ACOX) was significantly increased (+54.5% and +37.8%, P <.01 and P <.05, respectively), whereas the MBC of RAR and TR was significantly decreased (-16.0% and -23.4%, P <.01), as were the mRNA levels of RAR beta and TR alpha(1) beta(1) (-28.5% and -32.0%, P <.05). The level of RXR alpha mRNA was unchanged. In WAT, the mRNA level of PPAR gamma(2) was significantly increased after 28 days of cafeteria diet (+49.5%, P <.05) and the mRNA levels of RAR alpha and TR alpha(1) beta(1) significantly decreased (-22.3% and -31.0%, P <.05). These results as a whole showed that a high-fat diet can induce early modifications in the pattern of expression of nuclear receptors in the liver and the WAT. These modifications could be compatible with an early adaptive phenomenon. Further investigations are necessary to better understanding the link between the modifications of the pattern of expression of these receptors and plasticity of adipose tissue leading to the onset of obesity.
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PMID:Exposure to an obesity-inducing diet early affects the pattern of expression of peroxisome proliferator, retinoic acid, and triiodothyronine nuclear receptors in the rat. 1158 87

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.
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PMID:Expression of insulin target genes in skeletal muscle and adipose tissue in adult patients with growth hormone deficiency: effect of one year recombinant human growth hormone therapy. 1169 48

PPAR gamma is a major determinants of adipocyte differentiation and its activation by ligands including thiazolidinedione(TZDs) and the endogenous ligands induces transcription of the genes involving glucose and lipid metabolism. By the experiments using animal models with obesity-related phenotypes and PPAR gamma knockout mouse and the results of genetics study regarding on the mutations and SNPs in human, it is postulated that the PPAR gamma activation determines and modifies insulin sensitivity by the relationship between the degree of the activation and potency of ligands(agonists/antagonists). The modulation of the PPAR gamma activation by synthetic agonist/antagonists will be beneficial in the prevention and treatment of type 2 diabetes and obesity-related phenotypes.
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PMID:[A role of the PPAR gamma activation in insulin resistance]. 1171 3

Potent activation of PPAR gamma by thiazolidinediones(TZD) increases TG content of WAT, thereby decreasing TG content of liver/muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPAR gamma activity by PPAR gamma/RXR inhibitors decreases TG content of WAT/muscle/liver due to increased leptin and increase in fatty-acid combustion and decrease in lipogenesis, thereby ameliorating HF diet-induced obesity and insulin resistance. Moreover, PPAR gamma/RXR inhibitors decrease lipogenesis in WAT, while TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in FFA, and TNF alpha, and upregulation of adiponectin. We conclude that although by different mechanisms, both PPAR gamma/RXR inhibitors and PPAR gamma agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.
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PMID:[The molecular mechanisms by which PPAR gamma/RXR inhibitors improve insulin resistance]. 1171 15

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPAR gamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPAR gamma activity observed in heterozygous PPAR gamma-deficient mice or the Pro 12 Ala polymorphism in human PPAR gamma has been shown to prevent insulin resistance and obesity induced by a high-fat (HF) diet. We investigated whether functional antagonism toward PPAR gamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that moderate reduction of PPAR gamma with an RXR antagonist or a PPAR gamma antagonist decreases triglyceride (TG) content in white adipose tissue, skeletal muscle and liver. These inhibitors potentiate leptin's effects and stimulated adiponectin levels, which increases fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, severe reduction of PPAR gamma by treatment of heterozygous PPAR gamma-deficient mice with an RXR antagonist or a PPAR gamma antagonist depletes white adipose tissue and markedly decreases leptin and adiponectin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggest that appropriate functional antagonism of PPAR gamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.
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PMID:[PPAR gamma agonist and antagonist]. 1172 35

Cellular differentiation involves transcriptional responses to environmental stimuli. Adipocyte differentiation is inhibited under hypoxic conditions, indicating that oxygen (O(2)) is an important physiological regulator of adipogenesis. Hypoxia inhibits PPAR gamma 2 nuclear hormone receptor transcription, and overexpression of PPAR gamma 2 or C/EBP beta stimulates adipogenesis under hypoxia. Mouse embryonic fibroblasts deficient in hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) are refractory to hypoxia-mediated inhibition of adipogenesis. The HIF-1-regulated gene DEC1/Stra13, a member of the Drosophila hairy/Enhancer of split transcription repressor family, represses PPAR gamma 2 promoter activation and functions as an effector of hypoxia-mediated inhibition of adipogenesis. These data indicate that an O(2)-sensitive signaling mechanism regulates adipogenesis. Thus, agents that regulate HIF-1 activity or O(2) sensing may be used to inhibit adipogenesis and control obesity.
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PMID:Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. 1187 38


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