UMLS:C0028754 - FACTA Search

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

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

During the last 10 years, various adipocytokines have been described which influence insulin sensitivity profoundly and might, therefore, potentially link obesity and insulin resistance. Recently, monocyte chemoattractant protein (MCP)-1 was characterized as a novel adipose-secreted factor upregulated in obesity and insulin resistance that impairs insulin signaling in fat cells in vitro and can be found in atherosclerotic lesions. To clarify expression and regulation of this adipocytokine, MCP-1 mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance. Interestingly, MCP-1 synthesis was significantly downregulated between 43% and 68% during differentiation of 3T3-L1 preadipocytes. Furthermore, 10 ng/ml tumor necrosis factor alpha, 100 nM insulin, 500 ng/ml growth hormone (GH), and 30 ng/ml interleukin (IL)-6-induced MCP-1 mRNA by up to 124-, 23-, 8-, and 2.5-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 0.5 ng/ml GH and 30 ng/ml IL-6. In contrast, the glucocorticoid dexamethasone potently downregulated MCP-1 with significant suppression detectable at concentrations as low as 3 nM and as early as 2h after effector addition. Studies using pharmacological inhibitors suggested that the positive effects of GH and IL-6 on MCP-1 synthesis are at least in part mediated by janus kinase 2 and p44/42 mitogen-activated protein kinase. Taken together, our results show a differential regulation of MCP-1 mRNA by insulin resistance-inducing hormones and support the view that this adipocytokine might be an interesting novel candidate linking insulin resistance, obesity, and atherosclerosis. This adipocytokine could thus be a potential pharmacological target for the treatment of impaired insulin sensitivity.
...
PMID:Monocyte chemoattractant protein 1 expression is stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes. 1506 99

We reported previously that mice obese as a result of leptin deficiency (ob/ob) have enhanced ozone (O3)-induced airway hyperresponsiveness (AHR) and inflammation compared with wild-type (C57BL/6) controls. To determine whether this increased response to O3 was independent of the modality of obesity, we examined O3-induced AHR and inflammation in Cpe(fat) mice. These mice are obese as a consequence of a mutation in the gene encoding carboxypeptidase E (Cpe), an enzyme important in processing prohormones and proneuropeptides involved in satiety and energy expenditure. Airway responsiveness to intravenous methacholine, measured by forced oscillation, was increased in Cpe(fat) vs. wild-type mice after air exposure. In addition, compared with air exposure, airway responsiveness was increased 24 h after O3 exposure (2 ppm for 3 h) in Cpe(fat) but not in wild-type mice. Compared with air-exposed controls, O3 exposure increased bronchoalveolar lavage fluid (BALF) protein, IL-6, KC, MIP-2, MCP-1, and soluble TNF receptors (sTNFR1 and sTNFR2) as well as BALF neutrophils. With the exception of sTNFR1 and sTNFR2, all of these outcome indicators were greater in Cpe(fat) vs. wild-type mice. Serum sTNFR1, sTNFR2, MCP-1, leptin, and blood leukocytes were elevated in Cpe(fat) compared with wild-type mice even in the absence of O3 exposure, similar to the chronic systemic inflammation observed in human obesity. These results indicate that increased O3-induced AHR and inflammation are consistent features of obese mice, regardless of the modality of obesity. These results also suggest that chronic systemic inflammation may enhance airway responses to O3 in obese mice.
...
PMID:Augmented responses to ozone in obese carboxypeptidase E-deficient mice. 1600 59

In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of scWAT-infiltrating macrophages before surgery was higher in obese than in lean subjects (HAM56+/CD68+; 22.6 +/- 4.3 vs. 1.4 +/- 0.6%, P < 0.001). Typical "crowns" of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant decrease in macrophage number (-11.63 +/- 2.3%, P < 0.001), and remaining macrophages stained positive for the anti-inflammatory protein interleukin 10. Genes involved in macrophage attraction (monocyte chemotactic protein [MCP]-1, plasminogen activator urokinase receptor [PLAUR], and colony-stimulating factor [CSF]-3) and hypoxia (hypoxia-inducible factor-1alpha [HIF-1alpha]), expression of which increases in obesity and decreases after surgery, were predominantly expressed in the SVF. We show that improvement of the inflammatory profile after weight loss is related to a reduced number of macrophages in scWAT. MCP-1, PLAUR, CSF-3, and HIF-1alpha may play roles in the attraction of macrophages in scWAT.
...
PMID:Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. 1604 92

Resistin, an adipocyte-derived cytokine linked to insulin resistance and obesity, has recently been shown to activate endothelial cells (ECs). Using microarrays, we found that along with numerous other pro-atherosclerotic genes, resistin expression levels are elevated in the aortas of C57BL/6J apoE-/- mice; these findings led us to further explore the relation between resistin and atherosclerosis. Using TaqMan PCR and immunohistochemistry, we found that ApoE-/- mice had significantly higher resistin mRNA and protein levels in their aortas, and elevated serum resistin levels, compared to C57BL/6J wild-type mice. Incubation of murine aortic ECs with recombinant resistin increased monocyte chemoattractant protein (MCP)-1 and soluble vascular cell adhesion molecule (sVCAM)-1 protein levels in the conditioned medium. Furthermore, human carotid endarterectomy samples stained positive for resistin protein, while internal mammary artery did not show strong staining. Patients diagnosed with premature coronary artery disease (PCAD) were found to have higher serum levels of resistin than normal controls. In summary, resistin protein is present in both murine and human atherosclerotic lesions, and mRNA levels progressively increase in the aortas of mice developing atherosclerosis. Resistin induces increases in MCP-1 and sVCAM-1 expression in murine vascular endothelial cells, suggesting a possible mechanism by which resistin might contribute to atherogenesis. Finally, PCAD patients exhibited increased serum levels of resistin when compared to controls. These findings suggest a possible role of resistin in cardiovascular disease.
...
PMID:The potential role of resistin in atherogenesis. 1615 96

Adiponectin is an adipocyte-derived cytokine that plays a role in metabolic disorders such as obesity and diabetes mellitus. Recent work suggests that adiponectin may also affect the immune response, primarily acting as an anti-inflammatory factor. Given our observation that plasma and urine adiponectin levels are increased in SLE patients with inflammatory glomerulonephritis, we evaluated the effect of adiponectin on proinflammatory chemokines relevant to the pathogenesis of SLE nephritis. It was postulated that adiponectin would attenuate cytokine-induced chemokine expression. Cultured human microvascular endothelial cells and monocytes were treated with adiponectin, and IL-8 and MCP-1 levels were measured in the cell-culture supernatants by ELISA. Unexpectedly, full-length adiponectin significantly increased IL-8 and MCP-1 production, and did not abrogate cytokine-induced chemokine expression. Furthermore, adiponectin activated the proinflammatory transcription factor NF-kappaB. Chemokine induction by adiponectin was not mediated by the well-characterized adiponectin receptors involved in metabolic signaling, suggesting a novel receptor may be responsible for the inflammatory effect. We conclude that adiponectin may have pro- and anti-inflammatory effects, and its exact role in specific inflammatory diseases remains to be worked out.
...
PMID:Chemokine induction by the adipocyte-derived cytokine adiponectin. 1650

Adipose tissue is an active endocrine organ producing a variety of cytokines and chemokines, which may be involved in the deregulation of glucose and lipid homeostasis as well as in the inflammatory state observed in obesity. We have shown previously that differentiated human adipocytes secrete a variety of cytokines which are able to induce skeletal muscle insulin resistance. However, the regulation of these factors by anti-diabetic drugs has remained mainly undefined. Secretion of IL-6, IL-8, MIP-1alpha/beta, and MCP-1 by adipocytes was found to be downregulated by adiponectin. In parallel to adiponectin, the AMPK activator AICAR also decreased the secretion of most of the measured cytokines including IL-6 and MIP-1alpha/beta but not IL-8. In contrast, the thiazolidinedione troglitazone only slightly reduced cytokine secretion despite increasing the phosphorylation of AMPK. In conclusion, we show that adipocyte secretion is strongly inhibited by the anti-diabetic adipocyte hormone adiponectin, an effect that can also be mimicked by the AMPK activator AICAR. However, the PPARgamma agonist troglitazone is much less effective in reducing cytokine secretion.
...
PMID:Cytokine secretion by human adipocytes is differentially regulated by adiponectin, AICAR, and troglitazone. 1656 50

Recently, monocyte chemoattractant protein (MCP)-1 has been characterized as a novel adipocytokine upregulated in obesity and insulin resistance which impairs insulin signaling in muscle and fat in vitro. Growing evidence, on the other hand, suggests that increased activity of the sympathetic nervous system is an integral part in the development of insulin resistance. In the current study, the impact of the beta-adrenergic agonist isoproterenol on MCP-1 mRNA synthesis and secretion was determined in 3T3-L1 adipocytes. Interestingly, isoproterenol increased MCP-1 secretion 3-fold. Furthermore, 10 microM isoproterenol acutely induced MCP-1 mRNA by up to 5.3-fold in a time-dependent fashion with significant stimulation seen at concentrations as low as 0.3 microM effector. Studies using pharmacological inhibitors suggested that basal and isoproterenol-induced MCP-1 expressions are mediated via beta-adrenergic receptors and protein kinase A. Moreover, acute activation of adenylyl cyclase by forskolin was sufficient to mimic the effects of isoproterenol. Taken together, our results demonstrate that isoproterenol induces MCP-1 expression and secretion via a classical GS-protein-coupled pathway and support the notion that MCP-1 might be an interesting novel candidate linking obesity and insulin resistance.
...
PMID:Isoproterenol stimulates monocyte chemoattractant protein-1 expression and secretion in 3T3-L1 adipocytes. 1664 35

Leptin is an adipocyte-derived cytokine associated with obesity and inflammation recently shown to influence colon epithelial cell fate and colon inflammation. Thus, the purpose of this study is to investigate the influences of leptin exposure on the production of proinflammatory signals by a model of normal [YAMC (Apc+/+)] and preneoplastic [IMCE (ApcMin/+)] colon epithelial cells. Here, we characterize the production of specific CC and CXC chemokines by IMCE and YAMC cells using an antibody-based cytokine array. Further, since epithelial cells are hypothesized to be accessory to the inflammatory response, we assessed the ability of supernants from leptin-exposed colon epithelial cells to activate macrophage chemotaxis and nitric oxide production. Both YAMC and IMCE cells produced the following chemokines from the CC family; MCP-1, MIP-3alpha, TCA-3, CTACK and RANTES. These cell lines also produced the following CXC chemokines; MIP-2, CXCL18, KC and LIX. Conditioned media from leptin-treated YAMC and IMCE cells induced nitric oxide production by macrophages (P<0.05). However, only conditioned media from leptin-treated IMCE cells induced macrophage chemotaxis (P<0.05). These data imply that preneoplastic but not normal cells may selectively attract immune cells that promote their survival and transformation. Taken together with our previous data, we conclude that leptin promotes the proliferation of a model of preneoplastic cells (IMCE) and induces the production of chemokines which may activate macrophages and promote macrophage cell chemotaxis. These data provide a rational basis for leptin-induced cross-talk between preneoplastic epithelial cells and immune cells that may influence the promotional phase of carcinogenesis.
...
PMID:Leptin induces an Apc genotype-associated colon epithelial cell chemokine production pattern associated with macrophage chemotaxis and activation. 1689 27

The white adipose tissue, especially of humans, is now recognized as the central player in the mild inflammatory state that is characteristic of obesity. The question is how the increased accumulation of lipid seen in obesity causes an inflammatory state and how this is linked to the hypertension and type 2 diabetes that accompanies obesity. Once it was thought that adipose tissue was primarily a reservoir for excess calories that were stored in the adipocytes as triacylglycerols. In times of caloric deprivation these stored lipids were mobilized as free fatty acids and the insulin resistance of obesity was attributed to free fatty acids. It is now clear that in humans the expansion of adipose tissue seen in obesity results in more blood vessels, more connective tissue fibroblasts, and especially more macrophages. There is an enhanced secretion of some interleukins and inflammatory cytokines in adipose tissue of the obese as well as increased circulating levels of many cytokines. The central theme of this chapter is that human adipose tissue is a potent source of inflammatory interleukins plus other cytokines and that the majority of this release is due to the nonfat cells in the adipose tissue except for leptin and adiponectin that are primarily secreted by adipocytes. Human adipocytes secrete at least as much plasminogen activator inhibitor-1 (PAI-1), MCP-1, interleukin-8 (IL-8), and IL-6 in vitro as they do leptin but the nonfat cells of adipose tissue secrete even more of these proteins. The secretion of leptin, on the other hand, by the nonfat cells is negligible. The amount of serum amyloid A proteins 1 & 2 (SAA 1 & 2), haptoglobin, nerve growth factor (NGF), macrophage migration inhibitory factor (MIF), and PAI-1 secreted by the adipocytes derived from a gram of adipose tissue is 144%, 75%, 72%, 37%, and 23%, respectively, of that by the nonfat cells derived from the same amount of human adipose tissue. However, the release of IL-8, MCP-1, vascular endothelial growth factor (VEGF), TGF-beta1, IL-6, PGE(2), TNF-alpha, cathepsin S, hepatocyte growth factor (HGF), IL-1beta, IL-10, resistin, C-reactive protein (CRP), and interleukin-1 receptor antagonist (IL-1Ra) by adipocytes is less than 12% of that by the nonfat cells present in human adipose tissue. Obesity markedly elevates the total release of TNF-alpha, IL-6, and IL-8 by adipose tissue but only that of TNF-alpha is enhanced in adipocytes. However, on a quantitative basis the vast majority of the TNF-alpha comes from the nonfat cells. Visceral adipose tissue also releases more VEGF, resistin, IL-6, PAI-1, TGF-beta1, IL-8, and IL-10 per gram of tissue than does abdominal subcutaneous adipose tissue. In conclusion, there is an increasing recognition that adipose tissue is an endocrine organ that secretes leptin and adiponectin along with a host of other paracrine and endocrine factors in addition to free fatty acids.
...
PMID:Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. 1702 26

Obesity and obesity related diseases are a major public health problem. Recent studies have shown that fat tissue is not a simple energy storage organ, but exerts important endocrine and immune functions. These are achieved predominantly through release of adipocytokines, which include several novel and highly active molecules released abundantly by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines released possibly by inflammatory cells infiltrating fat, like TNF-alpha, IL-6, MCP-1 (CCL-2), IL-1. All of those molecules may act on immune cells leading to local and generalized inflammation and may also affect vascular (endothelial) function by modulating vascular nitric oxide and superoxide release and mediating obesity related vascular disorders (including hypertension, diabetes, atherosclerosis, and insulin resistance) but also cancer or non-alcoholic fatty liver diseases. Present review, in a concise form, focuses on the effects of major adipocytokines, characteristic for adipose tissue like leptin, adiponectin, resistin and visfatin on the immune system, particularly innate and adaptive immunity as well as on blood vessels. Macrophages and T cells are populating adipose tissue which develops into almost an organized immune organ. Activated T cells further migrate to blood vessels, kidney, brain and other organs surrounded by infiltrated fat leading to their damage, thus providing a link between metabolic syndrome, inflammation and cardiovascular and other associated disorders. Ceretain treatments may lead to significant changes in adipocytokine levels. For example include beta-2 adrenoreceptor agonists, thiazolidinediones as well as androgens lead to decrease of plasma leptin levels. Moreover future treatments of metabolic system associated disorders should focus on the regulation of adipocytokines and their modes of action.
...
PMID:Adipocytokines - novel link between inflammation and vascular function? 1722 78

1 2 3 4 5 6 7 8 9 10 Next >>