Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adiponectin, an adipokine secreted from adipocytes, plays a crucial role in the regulation of glucose and lipid metabolism. In the present study, we examine the role of the IL-6 family of cytokines in the expression of adiponectin in human adipocytes derived from human adipose tissue-derived stromal cells. Oncostatin M (OSM), but not IL-6, attenuated the expression level of adiponectin dose- and time-dependently, and the inhibitory effect of OSM on adiponectin expression was as potent as that of TNF-alpha. The OSM-induced down-regulation of adiponectin expression was correlated with the down-regulation of PPARgamma2 and lipoprotein lipase, markers for adipogenic differentiation, and depletion of intracellular lipid droplets, suggesting dedifferentiation of adipocytes in response to OSM. OSM induced phosphorylation of STAT1, and treatment of adipocytes with JAK3 inhibitor WHI-P131 or MEK inhibitor U0126, but not with JAK2 inhibitor AG490, prevented the activation of STAT1. Furthermore, the OSM-induced suppression of adiponectin expression and dedifferentiation of adipocytes were ameliorated by WHI-P131 or U0126, but not by AG490. These results suggest that OSM inhibits adiponectin expression by inducing dedifferentiation of adipocytes through signaling pathways involving JAK3 and MEK, but not JAK2.
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PMID:Oncostatin M decreases adiponectin expression and induces dedifferentiation of adipocytes by JAK3- and MEK-dependent pathways. 1708 97

Obesity is a major global health problem and is associated with low-grade inflammation and, in a number of cases, poor iron status. We speculated that the adipokine leptin might play a role in regulating iron metabolism in the overweight population because it shares a number of common biological features with IL-6, a major factor in the development of the anemia of chronic disease via its stimulatory actions on the production and release of the iron regulatory hormone hepcidin. To test this hypothesis, we exposed HuH7 human hepatoma cells to leptin and measured hepcidin mRNA expression by quantitative PCR. HuH7 cells were also transfected with a hepcidin promoter-luciferase reporter gene construct to investigate transcriptional regulation of hepcidin. In leptin-treated cells, hepcidin mRNA expression was enhanced significantly. Preincubation with a Janus kinase (JAK) 2 inhibitor significantly diminished this response. Hepcidin promoter activity was also increased in the presence of leptin. This effect was decreased either by mutation of the signal transducer and activator of transcription (STAT) 3 binding motif in the hepcidin promoter or by coexpressing a dominant-negative STAT3 mutant. These data suggest that leptin upregulates hepatic hepcidin expression through the JAK2/STAT3 signaling pathway. As a consequence, the increased production of leptin in overweight individuals might be a major contributor to the aberrant iron status observed in these population groups.
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PMID:Leptin increases the expression of the iron regulatory hormone hepcidin in HuH7 human hepatoma cells. 1795 71

Visfatin is a recently described new adipokine that is considered to bind to the insulin receptor and induce insulin action via signal transduction pathways distinct from those of insulin. This study investigated whether circulating plasma visfatin levels may be influenced by PPARy activation, as shown for adiponectin and other adipokines. Samples from a prospective single-blinded placebo-controlled three-month intervention study with rosiglitazone were retrospectively analysed. The samples were derived from 39 patients with type 2 diabetes mellitus suffering from coronary artery disease as confirmed by angiography (rosiglitazone arm: 18 men, 1 woman, age (mean +/- STD): 65 +/- 9 years, disease duration: 4.8 +/- 4.0 years, HbA1c: 7.3 +/- 1.3%; Placebo: 19 men, 1 woman, age: 64 +/- 10 years, disease duration: 5.1 +/- 6.5 years, HbA1c: 7.5 +/- 1.5%). Laboratory measurements for lipids, adiponectin, and visfatin were performed with validated tests. The baseline values were comparable for all observation markers. After three months, a significant increase in the adiponectin concentrations could be observed only in the rosiglitazone group (from: 6.9 +/- 0.9 mg/l to 16.5 +/- 1.5 mg/l, (p < 0.001) vs placebo: 7.8 +/- 6.3 mg/l to 8.0 +/- 0.8 mg/l, (n.s.), p < 0.001 between the groups at endpoint). No changes were seen in both treatment arms for the other observation parameters. In particular, no influence of rosiglitazone was seen on the visfatin concentrations (25.9 +/- 2.3 ng/ml to 25.8 +/- 1.9 ng/ml; Placbo: 26.9 +/- 5.4 ng/ml to 27.2 +/- 4.9 ng/ml, n.s.). Our investigation demonstrates that rosiglitazone has different effects on circulating concentrations of adiponectin and visfatin. Visfatin secretion is not regulated by PPARgamma and further research is required to investigate its role in insulin resistance.
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PMID:Impact of rosiglitazone on visfatin and adiponectin plasma concentrations in patients with type 2 diabetes and coronary artery disease. 1894 91

Acute exercise performance represents a major metabolic challenge for the skeletal muscle, but also for the liver as the most important source of energy. However the molecular adaptation of the liver to one single bout of exercise is largely unknown. C57BL/6 mice performed a 60 min treadmill run at high aerobic intensity. Liver, soleus and white gastrocnemius muscle were removed immediately after exercise. The single bout of exercise resulted in a very rapid and pronounced induction of hepatic metabolic enzymes and regulators of metabolism or transcription: glucose-6-phosphatase (G6Pase; 3-fold), pyruvate dehydrogenase kinase-4 (PDK4; 4.8-fold), angiopoietin-like 4 (2.1-fold), insulin receptor substrate (IRS)-2 (5.1-fold), peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha; 3-fold). In soleus and white gastrocnemius muscle the up-regulation of IRS-2 and PDK4 was less pronounced compared with the liver and no significant induction of PGC-1alpha could be detected at this early time point. Activation of AMPK was found in both liver and white gastrocnemius muscle as phosphorylation of Thr-172. The induction of endogenous insulin secretion by a glucose load directly after the exercise bout resulted in a significantly higher PKB/Akt phosphorylation in the liver of exercised mice. The markedly enhanced IRS-2 protein amount, and presumably reduced serine/threonine phosphorylation of the IRS proteins induced by the acute exercise could be responsible for this enhanced action of insulin. In conclusion, acute exercise induced a rapid and pronounced transcriptional adaptation in the liver, and regulated hepatic IRS proteins leading to improved cellular insulin signal transduction.
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PMID:Acute regulation of metabolic genes and insulin receptor substrates in the liver of mice by one single bout of treadmill exercise. 1900 Oct 47

Chemerin has recently been characterized as a novel adipokine playing a crucial role in adipocyte differentiation and insulin signalling. In the current study, the impact of insulin resistance-inducing and proinflammatory interleukin (IL)-1beta on chemerin protein secretion and mRNA expression was determined in 3T3-L1 adipocytes. Interestingly, IL-1beta significantly induced chemerin protein secretion almost 1.3-fold from 5.89 ng/ml (basal) to 7.52 ng/ml. Furthermore, chemerin mRNA synthesis was significantly stimulated by IL-1beta in a dose-dependent fashion with 1.5-fold induction seen at IL-1beta concentrations as low as 0.07 ng/ml and maximal 2.6-fold upregulation found at 2 ng/ml effector. Induction of chemerin mRNA by IL-1beta was time-dependent in both 3T3-L1 adipocytes and brown fat cells. Signalling studies suggested that Janus kinase 2, nuclear factor kappa B, p44/42 mitogen-activated protein kinase, and phosphatidylinositol 3-kinase are involved in IL-1beta-induced chemerin mRNA expression. Furthermore, recombinant chemerin downregulated insulin-stimulated glucose uptake. Taken together, we show that chemerin is upregulated in fat cells by IL-1beta and might modulate the effects of IL-1beta on adipocyte metabolism and insulin sensitivity.
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PMID:Interleukin-1beta induces the novel adipokine chemerin in adipocytes in vitro. 1923 30

The purpose of the current study was to examine the signal transduction pathways activated and adipokine secreted by kaempferitrin stimulation to adipocytes. Activation of insulin receptor beta and insulin receptor substrate 1 was tested in pull-down assays, and phosphorylation of Protein kinase B (PKB/akt) on ser 473 was measured by Western blot. Participation of phosphatidylinositol-3-kinase (PI3-K) in the pathway was tested by addition of wortmannin. GLUT4 translocation was measured on fractions of cell extracts, as well as by confocal imaging on fluorescent immunostained cells. Secreted and cellular adiponectin were measured by Western blot and ELISA. We showed that kaempferitrin treatment resulted in an up-regulated level of phosphorylation on insulin receptor beta and insulin receptor substrate 1, and ser473 site in PKB/akt. PI3-K acted up-stream of PKB/akt phosphorylation and GLUT4 translocation, as inhibitor of PI3-K wortmannin abolished both. GLUT4 translocated to membrane and GLUT4 protein level increased upon kaempferitrin stimulation. Kaempferitrin also stimulated more sustained adiponectin secretion than insulin did. This study provided evidence of the dual effects of kaempferitrin. It improved insulin resistance by the activation of the classical insulin transduction pathway, and increased adiponectin secretion.
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PMID:Kaempferitrin activates the insulin signaling pathway and stimulates secretion of adiponectin in 3T3-L1 adipocytes. 1932 66

Here, we examine the currently available information which supports that the adipokine, leptin, is a major player in the biology and pathology of mammalian skin and its appendages. Specifically, the potent metabolic effects of leptin and its mimetics may be utilized to improve, preserve and restore skin regeneration and hair cycle progression, and may halt or even partially reverse some aspects of skin ageing. Since leptin can enhance mitochondrial activity and biogenesis, this may contribute to the wound healing-promoting and hair growth-modulatory effects of leptin. Leptin dependent intracellular signalling by the Janus kinase 2 dependent signal transducer and activator of transcription 3, adenosine monophosphate kinase, and peroxisome proliferator-activated receptor (PPAR) gamma coactivator/PPAR converges to mediate mitochondrial metabolic activation and enhanced cell proliferation which may orchestrate the potent developmental, trophic and protective effects of leptin. Since leptin and leptin mimetics have already been clinically tested, investigative dermatology is well-advised to place greater emphasis on the systematic exploration of the cutaneous dimensions and dermatological potential of this pleiotropic hormone.
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PMID:Leptin and the skin: a new frontier. 1960 81

Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-kappaB in primary hepatocytes and pharmacological inhibition of NF-kappaB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with "STAT3 Inhibitor VI," however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-kappaB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.
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PMID:Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways. 1960 29

Adipokines may represent a mechanism linking insulin resistance to cardiovascular disease. We showed previously that homocysteine (Hcy), an independent risk factor for cardiovascular disease, can induce the expression and secretion of resistin, a novel adipokine, in vivo and in vitro. Since vascular smooth muscle cell (VSMC) migration is a key event in vascular disease, we hypothesized that adipocyte-derived resistin is involved in Hcy-induced VSMC migration. To confirm our hypothesis, Sprague-Dawley rat aortic SMCs were cocultured with Hcy-stimulated primary rat epididymal adipocytes or treated directly with increasing concentrations of resistin for up to 24 h. Migration of VSMCs was investigated. Cytoskeletal structure and cytoskeleton-related proteins were also detected. The results showed that Hcy (300-500 microM) increased migration significantly in VSMCs cocultured with adipocytes but not in VSMC cultured alone. Resistin alone also significantly increased VSMC migration in a time- and concentration-dependent manner. Resistin small interfering RNA (siRNA) significantly attenuated VSMC migration in the coculture system, which indicated that adipocyte-derived resistin mediates Hcy-induced VSMC migration. On cell spreading assay, resistin induced the formation of focal adhesions near the plasma membrane, which suggests cytoskeletal rearrangement via an alpha(5)beta(1)-integrin-focal adhesion kinase/paxillin-Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway. Our data demonstrate that Hcy promotes VSMC migration through a paracrine or endocrine effect of adipocyte-derived resistin, which provides further evidence of the adipose-vascular interaction in metabolic disorders. The migratory action exerted by resistin on VSMCs may account in part for the increased incidence of restenosis in diabetic patients.
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PMID:Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin. 2087 Oct 11

A dynamic cell-matrix interaction is crucial for a rapid cellular response to changes in the environment. Appropriate cell behavior in response to the changing wound environment is required for efficient wound closure. However, the way in which wound keratinocytes modify the wound environment to coordinate with such cellular responses remains less studied. We demonstrated that angiopoietin-like 4 (ANGPTL4) produced by wound keratinocytes coordinates cell-matrix communication. ANGPTL4 interacts with vitronectin and fibronectin in the wound bed, delaying their proteolytic degradation by metalloproteinases. This interaction does not interfere with integrin-matrix protein recognition and directly affects cell-matrix communication by altering the availability of intact matrix proteins. These interactions stimulate integrin- focal adhesion kinase, 14-3-3, and PKC-mediated signaling pathways essential for effective wound healing. The deficiency of ANGPTL4 in mice delays wound re-epithelialization. Further analysis revealed that cell migration was impaired in the ANGPTL4-deficient keratinocytes. Altogether, the findings provide molecular insight into a novel control of wound healing via ANGPTL4-dependent regulation of cell-matrix communication. Given the known role of ANGPTL4 in glucose and lipid homeostasis, it is a prime therapeutic candidate for the treatment of diabetic wounds. It also underscores the importance of cell-matrix communication during angiogenesis and cancer metastasis.
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PMID:Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing. 2072 46


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