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 resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

Uncoupling proteins (UCPs) are mitochondrial membrane transporters which are involved in dissipating the proton electrochemical gradient thereby releasing stored energy as heat. This implies a major role of UCPs in energy metabolism and thermogenesis which when deregulated are key risk factors for the development of obesity and other eating disorders. Recent studies have shown that the sympathetic nervous system, via norepinephrine (beta-adrenoceptors) and cAMP, as well as thyroid hormones and PPAR gamma ligands seem to be major regulators of UCP expression. From the three different UCPs identified so far by gene cloning UCP1 is expressed exclusively in brown adipocytes while UCP2 is widely expressed. The third analogue, UCP3, is expressed predominantly in human skeletal muscle and was found to exist in a long and a short form. At the amino acid level UCP2 has about 59% homology to UCP1 while UCP3 is 73% identical to UCP2. Both UCP2 and UCP3 were mapped in close proximity (75-150 kb) to regions of human chromosome 11 (11q13) that have been linked to obesity and hyper-insulinaemia. Furthermore, there is strong evidence that UCP2, by virtue of its ubiquitous expression, may be important for determining basal metabolic rate. Based on the published full-length cDNA sequence we have deduced the genomic structure of the human UCP2 (hUCP2) gene by PCR and direct sequence analysis. The hUCP2 gene spans over 8.4 kb distributed on 8 exons. The localization of the exon/intron boundaries within the coding region matches precisely the one found in the human UCP1 gene and is almost conserved in the recently discovered UCP3 gene as well. However, the size of each of the introns in the hUCP2 gene differs from its UCP1 and UCP3 counterparts. It varies from 81 bp (intron 5) to about 3 kb (intron 2). The high degree of homology at the nucleotide level and the conservation of the exon/intron boundaries among the three UCP genes suggests that they may have evolved from a common ancestor or are the result from gene duplication events. Mutational analysis of the hUCP2 gene in a cohort of 25 children of caucasian origin (aged 7-13) characterized by low BMR values revealed a point mutation in exon 4 (C to T transition at position 164 of the corresponding cDNA resulting in the substitution of an alanine residue by a valine at codon 55) and an insertion polymorphism in exon 8. The insertion polymorphism consists of a 45 bp repeat located 150 bp downstream of the stop codon in the 3'-UTR. The allele frequencies were 0.61 and 0.39 for the alanine and valine encoded alleles, respectively, and 0.71 versus 0.29 for the insertion polymorphism. Expression studies of the wildtype and mutant forms of UCP2 should clarify the functional consequences these mutations may have on energy metabolism and body weight regulation. In addition, mapping of the promoter region and the identification of putative promoter regulatory sequences should give insight into the transcriptional regulation of UCP2 expression--in particular by anyone of the above mentioned factors--in vitro and in vivo.
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PMID:Genomic organization and mutational analysis of the human UCP2 gene, a prime candidate gene for human obesity. 1007 61

Human obesity may have genetic causes, but determining the specific genes involved has been difficult. The peroxisome proliferator-activated receptor gamma (PPAR gamma) gene encodes a protein that plays an important role in the differentiation of fat cells. A mutation has been discovered in this gene which leads to a receptor that cannot be inactivated. This mutation, while probably rare, is associated with extreme obesity.
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PMID:A genetic mutation in PPAR gamma is associated with enhanced fat cell differentiation: implications for human obesity. 1039 Oct 18

1. Insulin resistance has been highlighted as a common causal factor for hypertension, hyperlipidaemia, diabetes mellitus and obesity, all of which are recognized to occur simultaneously, and a distinct clinical entity is defined as 'multiple risk factor syndrome'. 2. Recently, a new class of antidiabetic agents, thiazolidinediones (TZD) has been developed and has been shown to improve insulin resistance by binding and activating a nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma. 3. cDNA of rat PPAR gamma 1 and gamma 2 were cloned and gene regulation of PPAR gamma in rat mature adipocytes was examined. Hydrogen peroxide, an oxygen radical, which is recognized to be the common intracellular signal for multiple risk factors, potently down-regulated PPAR gamma mRNA expression in rat mature adipocytes. 4. Tumour necrosis factor (TNF)-alpha, which is considered to play a role in obesity-induced non-insulin-dependent diabetes mellitus and to augment oxidative stress, also suppressed PPAR gamma expression. 5. Thiazolidinediones dose-dependently recovered TNF-alpha-induced down-regulation of PPAR gamma mRNA expression. 6. The modulation of PPAR gamma expression by TZD can be one mechanism for the improvement of insulin resistance by TZD. 7. Vascular tone and remodelling are controlled by several vasoactive autocrine/paracrine factors produced by endothelial cells in response to several vascular injury stimuli, including hypertension. The PPAR gamma gene transcript was detected in cultured endothelial cells. 8. The administration of TZD stimulated the endothelial secretion of type-C natriuretic peptide, which is one of the natriuretic peptide family and is demonstrated by us to act as a novel endothelium-derived relaxing peptide. 9. Concomitantly, TZD significantly suppressed the secretion of endothelin, a potent endothelium-derived vasoconstricting peptide. 10. Thiazolidinediones can affect vascular tone and growth by modulating the production of endothelium-derived vasoactive substances to influence occurrence and progression of hypertension and atherosclerosis.
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PMID:Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor gamma. 1040 88

Agonist-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to cause adipocyte differentiation and insulin sensitivity. The biological role of PPAR gamma was investigated by gene targeting. Homozygous PPAR gamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Quite unexpectedly, heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma.
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PMID:PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. 1054 91

Several types of abnormal lipoprotein particles are observed in patients with insulin resistance: elevated VLDL-triglycerides, remnant lipoprotein, small dense LDL, reduced HDL-cholesterol. These patterns are caused by environmental and genetic factors that alter the lipoprotein metabolism. These lipoprotein abnormalities cause insulin resistance through several factors which decrease LPL and PPAR gamma, on the other hand increase ACS and MTP. It is considered that increased plasma level of FFA will closely associated with these factors and their regulations. Secretion of TNF-alpha from adipocytes increases in obesity and closely relates to the pathogenesis of insulin resistance. But the genetic mechanisms are not still clear. More studies about genetic factors which affect to lipoprotein metabolism will be needed and should be considered about the role on insulin resistance.
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PMID:[Molecular mechanism of insulin resistance in hyperlipidemia]. 1063 92

Obesity is a disease responsible for many serious complications. The sharp rise in the prevalence of obesity in many countries is supplying a powerful drive to basic and clinical research. Several genes responsible for monogenic murine obesity have recently been identified. One of these genes encodes the OB protein, or leptine, which is secreted by fat tissue and inhibits appetite by means of an effect on the hypothalamus. In humans, obese subjects carrying a mutation of this gene or of the leptine receptor have been identified. Several other genes implicated in human obesity have been mapped to chromosomes 1, 11, 18, and 20. Several transcription factors that control fat cell differentiation have been identified, such as C/ERB alpha, beta, and delta; ADD1/SREBP1, and PPAR gamma 2. It has been established that fat tissue can secrete many factors, including TNF alpha, CETP, IGF beta, TGF beta, PGE2, and LPA. Mitochondrial uncoupling proteins (UCPs) are recently characterized proteins capable of uncoupling respiration and contributing to energy expenditures. The hypothalamic neuropeptides and their receptors are a focus of active research. About ten of these neuropeptides have been identified.
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PMID:[Genetic and molecular aspects of obesity: recent data]. 1067 63

The peroxisomal 3-oxoacyl-CoA thiolase (thiolase) is the last enzyme involved in the beta-oxidation of fatty acids. The enzyme cleaves long chain fatty acyl-CoA to generate acetyl-CoA and shortened acyl-CoA. The enzyme is nuclear encoded, synthesized in the cytoplasm and transported into peroxisomes. The thiolase B gene is inducible by the peroxisome proliferator compounds, like other genes involved in beta-oxidation of fatty acids in peroxisomes. The importance of studying thiolase is that it generates acetyl-CoA which is the precursor for the synthesis of molecules like cholesterol and fatty acids. The structural and functional analysis of thiolase at molecular level may add to the knowledge of fatty acid metabolism and further the obesity phenomenon. It is known that several genes mediate lipid homeostasis in target organs like liver, adipose tissue and are regulated by peroxisome proliferator activated receptors (PPAR alpha and PPAR gamma). To elucidate the mechanism of induction of rat liver thiolase B gene, an upstream 2.8 kb fragment containing promoter element has been subcloned and partially sequenced. The sequence analysis revealed a putative PPRE (Peroxisome Proliferator Response Element) of AGACCT T TGAACC sequence at -681 to -668 [Kliever et al. (1992) Nature 358:771-774]. By transient expression of a luciferase reporter gene in HeLa cells, we conclude that the identified PPRE could be functional in induction of thiolase B gene, but other sequences of genes might be involved.
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PMID:Studies on regulation of the peroxisomal beta-oxidation at the 3-ketothiolase step. Dissection of the rat liver thiolase B gene promoter. 1070 52

We screened the peroxisome proliferator activated receptor gamma 2 (PPAR gamma 2) for sequence variants in 165 unrelated obese (BMI >/= 30 kg/m(2)) Caucasian women, and 49 normal weight Caucasian female controls (BMI < 27 kg/m(2)). The allele frequency of the Pro12Ala mutation was higher in obese(18.18%) than in normal weight women (8. 16%) (chi(2)((1)) = 5.68, P = 0.017). Among obese women, the Pro12Ala mutation lowered age of obesity onset (Pro/Pro, 13.2 +/- 9. 4 years; Pro/Ala+Ala/Ala 8.6 +/- 7.1 years, P = 0.005), was associated with lower fasting glucose and was protective against type II diabetes.
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PMID:The peroxisome proliferator-activated receptor gamma 2 Pro12Ala mutation is associated with early onset extreme obesity and reduced fasting glucose. 1087 98

Tumor necrosis factor alpha (TNF-alpha) has well-described effects on lipid metabolism in the context of acute inflammation, as in sepsis. Recently, increased TNF-alpha production has been observed in adipose tissue derived from obese rodents or human subjects and TNF-alpha has been implicated as a causative factor in obesity-associated insulin resistance and the pathogenesis of type 2 diabetes. Thus, current evidence suggests that administration of exogenous TNF-alpha to animals can induce insulin resistance, whereas neutralization of TNF-alpha can improve insulin sensitivity. Importantly, results from knockout mice deficient in TNF-alpha or its receptors have suggested that TNF-alpha has a role in regulating in vivo insulin sensitivity. However, the absence of TNF-alpha action might only partially protect against obesity-induced insulin resistance in mice. Multiple mechanisms have been suggested to account for these metabolic effects of TNF-alpha. These include the downregulation of genes that are required for normal insulin action, direct effects on insulin signaling, induction of elevated free fatty acids via stimulation of lipolysis, and negative regulation of PPAR gamma, an important insulin-sensitizing nuclear receptor. Although current evidence suggests that neutralizing TNF-alpha in type 2 diabetic subjects is not sufficient to cause metabolic improvement, it is still probable that TNF-alpha is a contributing factor in common metabolic disturbances such as insulin resistance and dyslipidemia.
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PMID:Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. 1087 50


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