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)

Type 2 diabetes is characterized by insulin resistance as well as impaired insulin secretion. Thus, the enhancement of insulin sensitivity is a possible treatment modality. The mechanism of insulin resistance is still unknown. However, some genetic backgrounds may be involved and modulated by environmental factors. Obesity is considered to be one of major factors to induce insulin resistance. Regarding mechanism of obesity-induced insulin resistance, the increased expression of Tumor necrosis factor alpha and abnormality in PTPase are postulated. Prolonged hyperglycemia also induces the impairment of insulin action, resulting in worsening glycemic control. Abnormal glucosamine biosynthesis and impaired receptor kinase are considered to be involved in the hyperglycemia-induced insulin resistance.
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PMID:[Molecular mechanism and clinical impact of insulin resistance in type 2 diabetes mellitus]. 1019 30

To further investigate the role of plasminogen activator inhibitor-1 (PAI-1) in adipose tissue physiology, the production and regulation of PAI-1 was determined in primary cultures of human preadipocytes. When expressed as production per cell and cultured under identical conditions, human preadipocytes from both visceral (omental) and sc depots of lean and obese individuals released significant, yet similar, amounts of PAI-1 protein into the conditioned medium. High steady-state PAI-1 messenger RNA (mRNA) concentrations were observed in visceral and sc preadipocytes, with the relative level of expression equivalent to beta-actin mRNA. Tumor necrosis factor alpha significantly decreased PAI-1 production in a concentration-dependent manner in both visceral and sc cultures, whereas transforming growth factor beta significantly elevated PAI-1 production, but only in sc preadipocytes from obese individuals. Addition of insulin had no effect on antigen levels in conditioned medium of preadipocyte cultures. Stimulation of the preadipocyte cultures with a defined medium resulted in differentiation to the adipocyte phenotype, as determined by flow cytometric analysis, verifying the cultures as human preadipocyte. These studies are the first to observe significant PAI-1 mRNA expression and protein production in primary cultures of a human adipose tissue cellular component, and they suggest that nascent adipocytes contribute significantly to the elevated plasma PAI-1 observed in obesity.
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PMID:Synthesis and secretion of plasminogen activator inhibitor-1 by human preadipocytes. 1048 91

Type 2 diabetes is characterized by insulin resistance in skeletal muscle. Since the molecular mechanism of insulin resistance is still unknown, insulin receptor dysfunction including abnormal IRS-1 phosphorylation is considered to be responsible for insulin resistance in some pathological states. Obesity is one of major factors to induce insulin receptor dysfunction. Regarding the mechanism of insulin resistance related obesity, the increased expression of Tumor necrosis factor alpha and abnormality in PTPase in skeletal muscle are postulated. As well as obesity, prolonged hyperglycemia, dyslipidemia and hypertension also induce the impairment of insulin receptor function. Therefore, the enhancement of insulin sensitivity by modulating these factors is a possible treatment modality in insulin resistant states.
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PMID:[Impairments of insulin receptor function in insulin resistant states]. 1070 49

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

Tumor necrosis factor alpha (TNF-alpha) is a multifunctional cytokine constitutively produced by adipose tissue that may mediate insulin resistance. Studies in Caucasian subjects have suggested that the G-308A transition in the 5' region of the TNF-alpha gene may be associated with insulin resistance and obesity. These factors have been proposed to underlie the clustering of type 2 diabetes, hypertension, and dyslipidemia found in the metabolic syndrome, the prevalence of which is reaching epidemic proportions in Hong Kong Chinese. We investigated the association of this gene polymorphism with the components of the metabolic syndrome including the lipid profile, as well as with the indices of obesity and insulin resistance as measured by the insulin-glucose product, in 440 Chinese subjects (healthy [27.5%] and overlapping groups with type 2 diabetes [54.1%], hypertension [38.8%], dyslipidemia [39.3%], or obesity [39.5%]). The frequency of the mutant A allele was 7.4% in 121 healthy controls and 9.0% in the total population. The mutation was not associated with any component of the metabolic syndrome or with the prevalence of albuminuria and retinopathy in these subjects. Furthermore, there was no difference in anthropometric measures, insulin resistance, or lipid levels between subjects with the GG genotype and those with the mutant allele. In summary, the TNF-alpha gene G-308A polymorphism is unlikely to play an important role in the development of these disorders in this population.
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PMID:Tumor necrosis factor alpha gene G-308A polymorphism in the metabolic syndrome. 1095 20

Increased expression of plasminogen activator inhibitor -1 (PAI-1) in adipose tissues is thought to contribute to both the cardiovascular and metabolic complications associated with obesity. Tumor necrosis factor alpha (TNF-alpha) is chronically elevated in adipose tissues of obese rodents and humans and has been directly implicated to induce PAI-1 in adipocytes. In this study, we used 3T3-L1 adipocytes to examine the mechanism by which TNF-alpha up-regulates PAI-1 in the adipocyte. Acute (3 h) and chronic (24 h) exposure of 3T3-L1 adipocytes to TNF-alpha induces PAI-1 mRNA by increasing the rate of transcription of the PAI-1 gene, and de novo protein synthesis is not required for this process. Although the p44/42 and PKC signaling pathways appear to be significant in the induction of PAI-1 mRNA in response to acute treatment with TNF-alpha, the more dramatic induction of PAI-1 mRNA observed in response to chronic exposure of adipocytes to TNF-alpha was mediated by these and additional signaling molecules, including p38, PI3-kinase, tyrosine kinases, and the transcription factor NF-kappaB. Moreover, the dramatic increase in PAI-1 observed after chronic exposure of adipocytes to TNF-alpha was accompanied by increased metabolic insulin resistance. Finally, we demonstrate that the PKC pathway is also central for PAI-1 induction in response to insulin and transforming growth factor-beta (TGF-beta), two additional molecules which are elevated in obesity and shown to directly induce PAI-1 in the adipocyte. The understanding of the mechanism of regulating PAI-1 expression in the adipocytes at the molecular level provides new insight to help identify novel targets in fighting the pathological complications of obesity.
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PMID:Molecular mechanisms of tumor necrosis factor-alpha-mediated plasminogen activator inhibitor-1 expression in adipocytes. 1592 93

The aim of the study was to determine whether lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) release from mononuclear cells (MNCs) is altered in obese reproductive-age women in response to hyperglycemia. Six obese and 8 age-matched normal-weight women (18-40 years) underwent a 2-hour 75-g oral glucose tolerance test. Tumor necrosis factor alpha release was measured from MNCs cultured in the presence of LPS after isolation from blood samples drawn fasting and 2 hours after glucose ingestion. Insulin resistance was derived by homeostasis model assessment of insulin resistance. Total body fat (%) and truncal fat (%) were determined by dual-energy absorptiometry. Obese women had a higher (P < .03) body mass index (34.1 +/- 1.1 vs 21.9 +/- 0.8 kg/m2), percentage of total body fat (42.4% +/- 1.3% vs 28.7% +/- 1.8%), and percentage of truncal fat (42.1% +/- 1.2% vs 24.7% +/- 2.2%). Homeostasis model assessment of insulin resistance was greater in the obese group (58.0 +/- 10.6 vs 27.8 +/- 4.3, P < .02). Fasting plasma C-reactive protein (7787 +/- 884 vs 236 +/- 79 ng/mL, P < .0001) and TNF-alpha (2.37 +/- 0.09 vs 0.54 +/- 0.04 pg/mL, P < .05) were both elevated in obese women. Hyperglycemia resulted in a suppression of LPS-stimulated TNF-alpha release from MNCs of normal-weight subjects (154 +/- 21 vs 57 +/- 28 pg/mL, P < .003), but no change in obese women (148 +/- 36 vs 173 +/- 49 pg/mL). The TNF-alpha response was different between groups (-97 +/- 21 vs +24 +/- 22 pg/mL, P < .003). There was also a positive association between the incremental change in MNC-derived TNF-alpha and percentage of truncal fat (r = 0.75, P < .002). In conclusion, these data suggest that there is an absence of the "normal" suppression of TNF-alpha in MNCs after hyperglycemia in obese women, and this response may contribute to impaired glucose disposal and insulin resistance.
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PMID:Altered tumor necrosis factor alpha release from mononuclear cells of obese reproductive-age women during hyperglycemia. 1642 37

Premenopausal women with polycystic ovary syndrome (PCOS) are at a much higher risk for excessive daytime sleepiness, fatigue, and insulin resistance than control women. Elevated levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) are presumably part of the pathogenesis of these clinical manifestations. Forty-two obese women with PCOS, 17 body mass index-comparable obese controls, and 15 normal-weight controls free from apnea participated in the study that included one 8-hour nighttime polysomnography, single morning cytokine plasma concentrations, and insulin resistance indices. Women with PCOS exhibited higher plasma concentrations of IL-6 than obese controls, who had intermediate values, or normal-weight controls, who had the lowest values (4.75 +/- 0.5 vs 3.65 +/- 0.4 vs 1.84 +/- 0.3 pg/mL, P < .01). Tumor necrosis factor alpha values were higher in PCOS and obese controls compared with normal-weight controls, but the difference was not statistically significant (4.05 +/- 0.3 vs 3.79 +/- 0.2 vs 3.14 +/- 0.2 pg/mL, P = .103). Based on backward regression analysis, IL-6 levels had a stronger association with the PCOS group than with the obese group, and the sleep or hypoxia variables did not make a significant contribution to either IL-6 or TNF-alpha. Both IL-6 and TNF-alpha correlated positively with body mass index (P < .01) in obese controls but not in women with PCOS. Furthermore, within the PCOS group, IL-6 and TNF-alpha correlated more strongly with indices of insulin resistance than obesity. We conclude that IL-6 levels are elevated in obese women with PCOS independently of obesity or sleep apnea and may represent a pathophysiologic link to insulin resistance.
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PMID:Plasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apnea. 1683 44

Catecholamines and natriuretic peptides stimulate human adipocyte lipolysis through an increase in cAMP and cGMP levels, resulting in phosphorylation and activation of hormone-sensitive lipase. A defect in hormone-sensitive lipase expression might contribute to the resistance to catecholamine-induced lipolysis observed in obesity. The respective roles and regulation of hormone-sensitive lipase and adipose triglyceride lipase in spontaneous and hormone-stimulated lipolysis remain to be determined. Tumor necrosis factor alpha stimulates triglyceride hydrolysis by multiple intracellular pathways acting on insulin signaling, G proteins and perilipins, and might contribute to enhanced plasma fatty acid levels in obesity. Characterization of the lipolytic pathways might provide novel strategies to decrease free fatty acid production and reverse insulin resistance and other obesity-related metabolic complications.
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PMID:Importance of TNFalpha and neutral lipases in human adipose tissue lipolysis. 1693 60

Tumor necrosis factor alpha (TNFalpha) is a cytokine secreted by macrophages and adipocytes that contributes to the low grade inflammation and insulin resistance observed in obesity. TNFalpha signaling decreases peroxisome proliferator-activated receptor gamma and glucose transporter isoform 4 (GLUT4) expression in adipocytes, impairing insulin action, and this is mediated in part by the yeast Ste20 protein kinase ortholog Map4k4. Here we show that Map4k4 expression is selectively up-regulated by TNFalpha, whereas the expression of the protein kinases JNK1/2, ERK1/2, p38 stress-activated protein kinase, and mitogen-activated protein kinase kinases 4/7 shows little or no response. Furthermore, the cytokines interleukin 1beta (IL-1beta) and IL-6 as well as lipopolysaccharide fail to increase Map4k4 mRNA levels in cultured adipocytes under conditions where TNFalpha elicits a 3-fold effect. Using agonistic and antagonistic antibodies and small interfering RNA (siRNA) against TNFalpha receptor 1 (TNFR1) and TNFalpha receptor 2 (TNFR2), we show that TNFR1, but not TNFR2, mediates the increase in Map4k4 expression. TNFR1, but not TNFR2, also mediates a potent effect of TNFalpha on the phosphorylation of JNK1/2 and p38 stress-activated protein kinase and their downstream transcription factor substrates c-Jun and activating transcription factor 2 (ATF2). siRNA-based depletion of c-Jun and ATF2 attenuated TNFalpha action on Map4k4 mRNA expression. Consistent with this concept, the phosphorylation of ATF2 along with the expression and phosphorylation of c-Jun by TNFalpha signaling was more robust and prolonged compared with that of IL-1beta, which failed to modulate Map4k4. These data reveal that TNFalpha selectively stimulates the expression of a key component of its own signaling pathway, Map4k4, through a TNFR1-dependent mechanism that targets the transcription factors c-Jun and ATF2.
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PMID:Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNFalpha receptor 1 signaling to c-Jun and activating transcription factor 2. 1750 68


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