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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma 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 PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin 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 suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.
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PMID:Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes. 1158 1

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor alpha (TNF-alpha) and several interleukins (IL), notably IL-1beta and IL-6. Other adipocyte products with 'immunological' actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-alpha and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-alpha mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual 'inflammatory' stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-alpha. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-alpha and IL-6 inhibit lipoprotein lipase, and TNF-alpha additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-alpha also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more 'trophic', and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor gamma). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of beta3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-alpha is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-alpha is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.
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PMID:Pro-inflammatory cytokines and adipose tissue. 1168 9

Expression of the gene encoding resistin, a low molecular weight protein secreted from adipose tissue postulated to link obesity and type II diabetes, was examined in 3T3-L1 adipocytes. Resistin mRNA was detected in 3T3-L1 cells by day 3 following induction of differentiation into adipocytes; by day 4 the level of resistin mRNA peaked and remained high. The PPARgamma activators, rosiglitazone or darglitazone, reduced the level of resistin mRNA. Dexamethasone upregulated resistin mRNA level, but no effect was observed with the beta(3)-adrenoceptor agonist, BRL 37344. A substantial reduction in resistin mRNA level was observed with insulin, which induced decreases at physiological concentrations. Insulin may be a major inhibitor of resistin production, and this does not support a role for resistin in insulin resistance.
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PMID:Inhibition by insulin of resistin gene expression in 3T3-L1 adipocytes. 1168 67

Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance.
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PMID:Insulin resistance and insulin sensitizers. 1168 68

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

Adiponectin (ApN) is thought to play a major role in the pathogenesis of the Metabolic Syndrome. Production of ApN and regulation of its related gene (apM1) have not yet been studied in human visceral adipose tissue. ApN was mainly associated with adipocyte membranes and abundantly secreted in medium from isolated adipocytes. apM1 gene expression, restricted to the adipocyte fraction of adipose tissue, decreased spontaneously when adipose explants were cultured in basal medium for 24 h while the expression of other adipose genes barely changed (PPARgamma, GAPDH) or increased (PAI-1). Unexpectedly, the fall of apM1 mRNA was prevented by the addition of actinomycin D, an inhibitor of transcription, or cycloheximide, an inhibitor of protein synthesis, and by reducing the amount of adipose tissue cultured per dish, thereby suggesting that a newly synthesized factor released by adipose tissue destabilizes apM1 mRNA. apM1 gene expression was also negatively regulated by glucocorticoids and positively by insulin and IGF-1. This regulation could contribute to the decreased apM1/ApN levels in insulin-resistant patients with obesity and the Metabolic Syndrome.
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PMID:Secretion of adiponectin and regulation of apM1 gene expression in human visceral adipose tissue. 1170 24

Type 2 diabetes is characterized by decreased secretion of insulin and insulin resistance. Thiazolidinediones are drugs to ameliorate insulin resistance. At present, only pioglitazone is available in Japan. The first drug of this category, troglitazone, has been withdrawn from market because of its liver toxicity in a few patients. The decrease in fasting plasma glucose begins within 2 weeks and reaches the nadir in 8-12 weeks. Plasma insulin levels usually decrease together with plasma glucose. Thiazolidinedione drugs are effective in about 50% of type 2 diabetic patients. The efficacy is higher in patients with obesity, high insulin levels and in aged people and females. The mechanism is thought to be mediated by activation of a nuclear receptor, PPAR-gamma, which is most abundantly expressed in the adipose tissue. Current concept is that, when PPAR-gamma is activated by these drugs, the number of small adipocytes is increased to replace large adipocytes, thereby decreasing the release of TNF-alpha and FFA from adipose tissue. However, there seems to be a complex relationship between the activity of PPAR-gamma and insulin sensitivity. The effect of these new category drugs should be monitored carefully on a long-term basis.
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PMID:[Insulin sensitizer drugs, thiazolidinediones: current state and prospect]. 1171 93

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

The pivotal role of peroxisome proliferator-activated receptor gamma (PPARgamma) in the liver, although important for the regulation of genes involved in glucose and lipid metabolism, has generally not been fully appreciated. This may be due to the fact that PPARgamma, in contrast to PPARalpha or PPARdelta, is not abundantly expressed in liver under normal conditions. However, recent findings have revealed that in several murine models of obesity and type 2 diabetes mellitus (T2DM), PPARgamma mRNA and receptor protein are highly up-regulated in the liver, and that the receptor causes increased transcriptional activity as demonstrated by the activation of PPARgamma-responsive genes in the liver. Prolonged treatment of obese and diabetic mice, but not of lean control mice, with the selective PPARgamma ligands and activators, thiazolidinediones (TZDs), including troglitazone, rosiglitazone, or pioglitazone, has resulted in the development of severe hepatic centrilobular steatosis. In contrast to these effects in hepatocytes, TZD-mediated effects on Kupffer cells (down-regulation of proinflammatory cytokines) seem to be PPARgamma-independent. In view of the findings that sustained hepatic steatosis can lead to steatohepatitis and/or fibrosis and that troglitazone (but not the other TZDs) has been associated with rare but serious hepatotoxicity in patients, further insight into PPARgamma-mediated versus non-PPARgamma-mediated effects of TZDs is desirable. It is concluded that liver-specific effects associated with TZD antidiabetics may become relevant under conditions of selective PPARgamma up-regulation in the liver. Therefore, receptor expression in human liver tissue of obese and T2DM patients should deserve increased consideration in the future.
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PMID:Toxicological consequences of altered peroxisome proliferator-activated receptor gamma (PPARgamma) expression in the liver: insights from models of obesity and type 2 diabetes. 1175 68

Numerous evidences have demonstrated the relationship between high fat diets and onset and/or progression of several diseases associated with obesity. Moreover, several studies have shown that dietary fat generally increases cancer risk. Fatty acids also play a crucial role in the development of these pathologies. The nuclear receptors PPARgamma and PPARdelta are molecular targets for fatty acids. These receptors exert opposite actions in the tumorigenesis process. Indeed, whereas fatty acids-activated PPARdelta is implicated in cellular proliferation and appears to play some role in tumor onset, the activation of PPARgamma by fatty acids or some of their metabolites, seems to counteract tumor progression. Then, PPARgamma and PPARdelta could constitute new potential pharmaceutical targets for cancer treatment.
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PMID:[PPARdelta and PPARgamma: roles in fatty acids signalling, implication in tumorigenesis]. 1184 22


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