Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the adipocyte-derived protein resistin, which is thought to play a key role in the development of insulin resistance in vivo, is regulated by a variety of hormones and mediators, including insulin and TNFalpha. Here we describe our use of adenovirus-mediated gene transfer to determine which transcription factors and signaling pathways affect resistin expression in 3T3-L1 adipocytes. We found that resistin expression was enhanced by overexpression of C/EBPalpha and suppressed by C/EBPzeta, a negative regulator of C/EBPalpha. Additionally, C/EBPalpha induced resistin even in L6 myocytes. Overexpression of PPARgamma markedly reduced resistin expression, whereas PPARalpha had no significant effect. Resistin expression was markedly suppressed by overexpression of the PI3-kinase p110alpha catalytic subunit and by Akt. Finally, overexpression of MEK1, MKK6, or MKK7 suppressed resistin expression. These findings indicate that resistin expression is regulated by C/EBPalpha and PPARgamma, partly via modulation of signal transduction in the PI3-kinase and MAP kinase pathways.
 ...
PMID:Resistin is regulated by C/EBPs, PPARs, and signal-transducing molecules. 1243 85

Elevated levels of resistin have been proposed to cause insulin resistance and therefore may serve as a link between obesity and type 2 diabetes. However, its role in skeletal muscle metabolism is unknown. In this study, we examined the effect of resistin on insulin-stimulated glucose uptake and the upstream insulin-signaling components in L6 rat skeletal muscle cells that were either incubated with recombinant resistin or stably transfected with a vector containing the myc-tagged mouse resistin gene. Transfected clones expressed intracellular resistin, which was released in the medium. Incubation with recombinant resistin resulted in a dose-dependent inhibition of insulin-stimulated 2-deoxyglucose (2-DG) uptake. The inhibitory effect of resistin on insulin-stimulated 2-DG uptake was not the result of impaired GLUT4 translocation to the plasma membrane. Furthermore, resistin did not alter the insulin receptor (IR) content and its phosphorylation, nor did it affect insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation, its association with the p85 subunit of phosphatidylinositol (PI) 3-kinase, or IRS-1-associated PI 3-kinase enzymatic activity. Insulin-stimulated phosphorylation of Akt/protein kinase B-alpha, one of the downstream targets of PI 3-kinase and p38 MAPK phosphorylation, was also not affected by resistin. Expression of resistin also inhibited insulin-stimulated 2-DG uptake when compared with cells expressing the empty vector (L6Neo) without affecting GLUT4 translocation, GLUT1 content, and IRS-1/PI 3-kinase signaling. We conclude that resistin does not alter IR signaling but does affect insulin-stimulated glucose uptake, presumably by decreasing the intrinsic activity of cell surface glucose transporters.
 ...
PMID:Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. 1261 60

Beyond their effects on central metabolic functions, leptin, resistin, and adiponectin have profound effects on a number of other physiologic processes, including immune function and inflammation. Although leptin, resistin, and adiponectin are produced in human placenta and adipose tissue, their immunoregulatory actions in these tissues are not known. Therefore, the aim of this study was to determine the effect of leptin, resistin, and adiponectin on the release of proinflammatory mediators in human placenta and sc adipose tissue. Samples were obtained from normal pregnancies at the time of cesarean section. Tissue explants (n = 5) were incubated in the absence (basal control) or presence of a leptin (1, 10, and 100 ng/ml), resistin (1, 10, and 100 ng/ml), and adiponectin (0.1 and 0.5 microg/ml). After 6 h incubation, the medium was collected, and the release of IL-1beta, IL-6, TNFalpha, prostaglandin (PG)F2alpha and PGE2 was quantified by ELISA. There was no effect of resistin on proinflammatory cytokine or prostaglandin release; however, leptin at 100 ng/ml and adiponectin at 0.1 and/or 0.5 microg/ml significantly increased the release of IL-1beta, IL-6, TNFalpha, and PGE2 from human placenta and adipose tissue. Although both leptin and adiponectin significantly increased PGF2alpha release from human placenta, there was no effect of these hormones on PGF2alpha release from adipose tissue. Furthermore, this leptin- and adiponectin-induced proinflammatory response could be abrogated by treatment with the antiinflammatory ERK1/2 MAPK inhibitor U0126, the peroxisomal proliferator-activated receptor-gamma ligand troglitazone, and the nuclear factor-kappaB inhibitor BAY 11-7082. Collectively, these data indicate that leptin and adiponectin activate proinflammatory cytokine release and phospholipid metabolism in human placenta and adipose tissue, and antiinflammatory agents can abrogate leptin- and adiponectin-induced inflammation.
 ...
PMID:Leptin and adiponectin stimulate the release of proinflammatory cytokines and prostaglandins from human placenta and maternal adipose tissue via nuclear factor-kappaB, peroxisomal proliferator-activated receptor-gamma and extracellularly regulated kinase 1/2. 1590 15

The novel insulin receptor substrate protein APS is highly expressed in insulin-sensitive tissues and plays an important role in insulin-mediated glucose uptake and GLUT4 translocation via the Cbl/CAP pathway. Tyrosine phosphorylation of APS leads to recruitment of c-Cbl and Crk, while overexpression of APS mutant inhibits GLUT4 translocation in response to insulin, but the regulation of APS expression in skeletal muscle has not been previously reported. L6 myoblasts were differentiated in 2% FBS and serum starved for 24h prior to stimulation for 24h with either insulin 1 microM (n=6), rosiglitazone 10 microM (n=6), resistin 500 nM (n=6) or the MAP kinase inhibitor PD098059 50 microM (n=6) for 30 min, followed by insulin 1 microM for 24h. Semi-quantitative real-time RT-PCR was used to determine the expression of APS mRNA relative to the control gene TF2D. APS expression was markedly upregulated by myoblast differentiation (0.55+/-0.08 versus 1.14+/-0.08, p=0.001), and this effect was augmented by addition of rosiglitazone 10 microM for 24h to the differentiated myotubes (1.50+/-0.09, p=0.025). Insulin caused a 3.1-fold decrease in APS mRNA expression (0.37+/-0.01 versus 1.14+/-0.08, p=0.001), an effect that was attenuated by the MAP kinase inhibitor PD098059 (0.80+/-0.03, p=0.001). Exposure to resistin produced a modest decrease (1.4-fold) in myotube expression of APS (0.8+/-0.09, p=0.025). In conclusion, this is the first study to show that exposure to insulin markedly reduces the expression of APS in skeletal muscle via a MAP kinase dependent pathway, whereas myocyte differentiation and rosiglitazone increase APS expression. Changes in APS expression may be important in the aetiology and therapeutic reversal of insulin resistance in skeletal muscle.
 ...
PMID:Contrasting effects of insulin and cellular differentiation on expression of the novel insulin receptor substrate APS in skeletal muscle. 1616 63

Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. Because the serum concentration and intestinal expression level of RELMbeta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMbeta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELMbeta overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia, fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMbeta transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMbeta, suggesting the insulin resistance-inducing effect of RELMbeta to be direct. Furthermore, it was shown that RELMbeta acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This increased basal p38 phosphorylation level was also observed in the livers of RELMbeta transgenic mice. In conclusion, RELMbeta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMbeta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELMbeta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.
 ...
PMID:Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet. 1624 41

The key feature of metabolic syndrome, a cluster of metabolic and cardiovascular disorders, is systemic insulin resistance, which is associated with dysregulated endothelial nitric-oxide synthase (eNOS). Stress signaling induced by inflammation can inhibit insulin signaling. However, molecular mechanisms for the cross-talk between stress signaling and insulin resistance are only partially understood. Resistin, an adipokine/cytokine, is involved in inflammatory processes that could lead to insulin resistance status and vascular diseases. In the current study, we observed that resistin inhibited insulin signaling and eNOS activation in endothelial cells. Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression by resistin may mediate the inhibitory effects. Activated stress signaling p38 MAPK, but not JNK, is involved in PTEN up-regulation. We further found that p38 target transcriptional factor activating transcription factor-2 (ATF-2) bound to ATF sites in the PTEN promoter. The phosphorylation/activation of ATF-2 and its binding to PTEN promoter were increased by resistin treatment. In summary, up-regulation of PTEN is involved in the inhibitory effects of resistin on insulin signaling and eNOS activation in endothelial cells. Resistin induces PTEN expression by activating stress signaling p38 pathway, which may activate target transcription factor ATF-2, which in turn induces PTEN expression. Our findings suggest that resistin-mediated inhibition of insulin signaling and eNOS activation may contribute to cardiovascular diseases.
 ...
PMID:Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells. 1641 68

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.
 ...
PMID:Recent advances in the relationship between obesity, inflammation, and insulin resistance. 1661 57

Resistin is known as an adipocyte-specific secretory hormone that can cause insulin resistance and decrease adipocyte differentiation. It can be regulated by sexual hormones, but the mechanism of estrogen's actions is still not clear. Using 3T3-L1 adipocytes, we found that 17 beta-estradiol (E2) up-regulated resistin mRNA expression in a dose- and time-dependent manner. The concentration of E2 that increased resistin mRNA levels by 100-250% was approximately 1 nM for a range of 1-24 h of treatment. Treatment with either actinomycin D or cycloheximide prevented E2-stimulated resistin mRNA expression, suggesting that the effect of E2 requires new mRNA and protein synthesis. Although E2 was shown to increase activities of the estrogen receptor (ER) and MAPK kinase 1 and the association of nuclear ER alpha and CCAAT/enhancer binding protein-alpha with the resistin gene promoter, signaling was demonstrated to be blocked by pretreatment with either ICI182780 or PD98059. Neither SB203580 nor LY294002 changed the E2-increased levels of resistin mRNA, but they respectively inhibited E2-stimulated phosphorylation of p38 MAPK and Akt. These results imply the ER alpha, ERK, and CCAAT/enhancer binding protein- are necessary for the E2 stimulation of transcription from the resistin promoter. Moreover, PD98059, but not SB203580 or LY294002, antagonized E2-increased resistin protein release. These data suggest that E2 likely modifies the distribution of the resistin protein between the intracellular and extracellular compartments via an ERK-dependent pathway.
 ...
PMID:17 beta-estradiol stimulates resistin gene expression in 3T3-L1 adipocytes via the estrogen receptor, extracellularly regulated kinase, and CCAAT/enhancer binding protein-alpha pathways. 1674 Sep 79

The heart is a resistin target tissue and can function as an autocrine organ. We sought to investigate whether cyclic mechanical stretch could induce resistin expression in cardiomyocytes and to test whether there is a link between the stretch-induced TNF-alpha and resistin. Neonatal Wistar rat cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation at 60 cycles/min. Cyclic stretch significantly increased resistin protein and mRNA expression after 2-18 h of stretch. Addition of PD-98059, TNF-alpha antibody, TNF-alpha receptor antibody, and ERK MAP kinase small interfering RNA 30 min before stretch inhibited the induction of resistin protein. Cyclic stretch increased, whereas PD-98059 abolished, the phosphorylated ERK protein. Gel-shift assay showed a significant increase in DNA-protein binding activity of NF-kappaB after stretch, and PD-98059 abolished the DNA-protein binding activity induced by cyclic stretch. DNA binding complexes induced by cyclic stretch could be supershifted by p65 monoclonal antibody. Cyclic stretch increased resistin promoter activity, whereas PD-98059 and p65 antibody decreased resistin promoter activity. Cyclic stretch significantly increased TNF-alpha secretion from myocytes. Recombinant resistin protein and conditioned medium from stretched cardiomyocytes reduced glucose uptake in cardiomyocytes, and recombinant small interfering RNA of resistin or TNF-alpha antibody reversed glucose uptake. In conclusion, cyclic mechanical stretch enhances resistin expression in cultured rat neonatal cardiomyocytes. The stretch-induced resistin is mediated by TNF-alpha, at least in part, through ERK MAP kinase and NF-kappaB pathways. Glucose uptake in cardiomyocytes was reduced by resistin upregulation.
 ...
PMID:Mechanical stretch enhances the expression of resistin gene in cultured cardiomyocytes via tumor necrosis factor-alpha. 1757 61

Adipose tissue secretes a wide range of hormones named adipokines, and these may play a role in obesity-related inflammation. Adiponectin is an exceptional adipokine because low plasma concentrations are associated with obesity, type 2 diabetes, and cardiovascular diseases. It has been observed that plasma adiponectin concentrations are elevated during inflammatory conditions like preeclampsia and arthritis. Nuclear factor-kappaB (NF-kappaB) is an essential transcription factor for expression of inflammation-related proteins. We have used U937 cells stably transfected to express luciferase under the control of NF-kappaB to examine if adiponectin may modulate NF-kappaB activity. Physiological concentrations of native adiponectin induced NF-kappaB activity. This effect was relatively strong compared with proinflammatory adipokines like leptin, resistin, and IL-6. The enhanced NF-kappaB activity was attributed to the high molecular weight adiponectin isoforms. NF-kappaB was not activated by mutated adiponectin that is unable to form high molecular weight complexes. Furthermore, the C-terminal fragment, globular adiponectin, markedly increased NF-kappaB reporter activity, cytokine release, and mRNA expression of inflammation marker genes, at higher levels than stimulation with TNF-alpha and lipopolysaccharide. NF-kappaB activation by globular adiponectin was not affected by antibody inhibition of toll-like receptor 4 or TNF receptors 1 and 2 but was attenuated by inhibitors of p38 MAPK, phosphatidylinositol 3-kinase, and protein kinase C. Analyses of the p65 subunit of NF-kappaB in different leukocyte cell lines showed activation of two monocytic cell lines (U937 and THP-1) by native and globular adiponectin. Our results indicate that adiponectin has proinflammatory properties in monocytic cells.
 ...
PMID:Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. 1770 46


1 2 3 4 5 6 7 Next >>