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

Obesity is an important risk factor for esophageal adenocarcinoma (EAC), and elevated serum leptin is characteristic of obesity. We hypothesized that leptin may have biological effects in promoting esophageal adenocarcinoma and examined the effects of leptin on the OE33 Barrett's-derived EAC line. Proliferation was assessed by dimethylthiazoldiphenyltetra-zoliumbromide and 5-bromo-2'-deoxyuridine incorporation assays and apoptosis by ELISA of intracellular nucleosomes. Intracellular signaling was examined using specific pharmacological inhibitors and direct detection of phosphorylated active kinases. Expression of the long and short leptin receptors by OE33 cells was confirmed by RT-PCR, Western blotting and immunocytochemistry. Leptin stimulated OE33 cell proliferation in a dose-dependent manner and inhibited apoptosis. These effects were dependent on cyclooxygenase (COX)-2 and replicated by adding prostaglandin E2 (PGE2). The effects of PGE2 and leptin were abolished by the EP-4 antagonist AH23848. ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and Janus tyrosine kinase (JAK)-2 were activated upstream of COX-2 induction, whereas the epidermal growth factor receptor and c-Jun NH2-terminal kinase (JNK) were downstream of COX-2. The activation of ERK and Akt but not p38 MAPK was JAK2 dependent. PGE2 stimulated phosphorylation of JNK in an EGF receptor-dependent manner, and activation of the epidermal growth factor receptor required protein kinase C, src, and matrix metalloproteinase activities. We conclude that leptin stimulates cell proliferation and inhibits apoptosis in OAC cells via ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and JAK2-dependent activation of COX-2 and PGE2 production. Subsequent PGE2-mediated transactivation of the epidermal growth factor receptor and JNK activation are essential to the leptin effects. These effects may contribute to the greatly increased risk of esophageal adenocarcinoma in obesity.
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PMID:Leptin stimulates proliferation and inhibits apoptosis in Barrett's esophageal adenocarcinoma cells by cyclooxygenase-2-dependent, prostaglandin-E2-mediated transactivation of the epidermal growth factor receptor and c-Jun NH2-terminal kinase activation. 1674 Sep 77

Obesity is a common disorder and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity in Western-type societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems in the development of obesity. These studies support a role of both systems in adipogenesis and obesity; the role of specific members of these families, however, remains to be determined.
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PMID:Role of the fibrinolytic and matrix metalloproteinase systems in development of adipose tissue. 1717 99

It has long been recognized that leptin, a hormone made by adipocytes, is an important circulating signal for the regulation of body weight. In addition, matrix metalloproteinase (MMP), especially MMP-2, an adipocyte-secreted protein which promotes multi-cellular adipose clusters, is up-regulated in obesity. The present study is designed to evaluate whether trans-10,cis-12 conjugated linoleic acid (t-CLA) can suppress leptin-induced MMP-2 secretion in 3T3-L1 cells. The result showed that expressions of adipocyte marker proteins were significantly reduced by t-CLA-treated cultures, but not by linoleic acid (LA)-treated ones. Interestingly, MMP-2 secretion was significantly increased by leptin-treated cultures, thereby leading to accelerate adipocyte differentiation, indicating that MMP-2 was a necessary mediator of adipogenesis. However, increasing concentration of t-CLA significantly reduced leptin-induced MMP-2 secretion and triglyceride (TG) content. These findings provide support for a role for t-CLA in the regulation of metabolism in leptin-induced adipose tissue development.
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PMID:Leptin-induced matrix metalloproteinase-2 secretion is suppressed by trans-10,cis-12 conjugated linoleic acid. 1738 21

Obesity is a major risk factor for the development of hypertension. Recent studies have suggested that leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is related to the pathogenesis of obesity-related hypertension. However, the signaling mechanisms underlying the effects of leptin remain to be extensively examined. In this study, we found that leptin induced extracellular signal-regulated kinase phosphorylation and endothelin-1 expression in rat aortic smooth muscle cells. Both PD98059 and U0126, inhibitors of the upstream activator of mitogen-activated protein kinase kinase, inhibited augmentation of endothelin-1 expression stimulated with leptin. Leptin induced significant tyrosine phosphorylation of epidermal growth factor receptor, which was significantly attenuated by two inhibitors, an epidermal growth factor receptor tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of epidermal growth factor receptor transactivation induced by leptin is dependent on proteolytically released epidermal growth factor receptor ligands. Pretreatment of cells with AG1478 significantly reduced the degree of phosphorylation of extracellular signal-regulated kinase and endothelin-1 expression. Our results reveal that epidermal growth factor receptor transactivation is involved in the leptin signaling pathway in vascular smooth muscle cells, which may be related to the increased risk of hypertension and other cardiovascular diseases in obese subjects.
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PMID:Leptin stimulates endothelin-1 expression via extracellular signal-regulated kinase by epidermal growth factor receptor transactivation in rat aortic smooth muscle cells. 1767 88

Development of obesity is associated with substantial modulation of adipose tissue structure, involving adipogenesis, angiogenesis, and extracellular matrix remodelling. These processes require proteolytic activity, provided mainly by the fibrinolytic (plasminogen/plasmin), matrix metalloproteinase, and ADAM/ADAMTS systems. In early-stage development of adipose tissue, adipogenesis is tightly associated with angiogenesis. Thus, adipose tissue explants trigger blood vessel formation, and in turn adipose tissue endothelial cells promote pre-adipocyte differentiation. Modulation of angiogenesis and of proteolytic systems may have the potential to impair adipose tissue development.
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PMID:Angiogenesis and obesity. 1800 85

Obesity is a common disorder, and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity in Western-type societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems in the development of obesity. These studies support a role of both systems in adipogenesis and obesity, and suggest that modulation of proteolytic activity may affect development of adipose tissue.
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PMID:Role of proteolysis in development of murine adipose tissue. 1827 77

In order to investigate whether weight loss can lead to improvement of the mononuclear cell (MNC) proinflammatory state, 21 nondiabetic obese women with mean age 34+/-2 years (mean+/-s.e.m.) and BMI 32.5+/-1.2 kg/m2 were enrolled in a 12-week caloric restriction and light exercise-based weight loss program. Ten lean women served as controls. Reverse transcription-PCR of proinflammatory cytokines and adipocytokines as well as homeostasis model assessment of insulin resistance (HOMA-IR) were determined before and after weight reduction. Nuclear factor kappaB (NF-kappaB) binding to DNA and inhibitors of NF-kappaB (IkappaB-alpha and IkappaB-beta) obtained from peripheral MNCs were measured. Overall, subjects lost a mean of 4.0+/-0.4 kg (5.0+/-0.3% of their initial body weight) (P<0.01). In addition to significant reductions in BMI, fasting glucose and insulin concentrations, mean serum high-sensitivity C-reactive protein (hs-CRP), migration inhibitor factor (MIF), leptin and visfatin levels decreased by 49.0, 66.6, 17.2, and 50.2%, respectively (all P<0.05), while adiponectin concentrations rose by 33.9% (P<0.05). The DNA binding of the transcriptionally active NF-kappaB from (p65/p50) decreased by 38.1% (P<0.05). Elevated levels of mRNA of NF-kappaB related proinflammatory genes, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), MIF, and matrix metalloproteinase-9 (MMP-9), decreased significantly after weight loss. Although mRNA expression of Rel-A, p105, IkappaB-alpha, IkappaB-beta decreased significantly, their protein levels did not change after weight loss. As a group, NF-kappaB binding activity correlated with HOMA-IR (r=0.332, P=0.049) and marginally with values of BMI (r=0.308, P=0.059). In conclusion, weight loss by 5% of initial weight in nondiabetic obese women led to significant improvement in activated intranuclear NF-kappaB binding as well as several transcriptions of proinflammatory genes regulated by NF-kappaB.
Obesity (Silver Spring) 2008 May
PMID:Effect of weight loss on proinflammatory state of mononuclear cells in obese women. 1939 76

Guggulsterone is a plant sterol that is used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on fibroblast-like synoviocytes (FLS) has not yet been reported. Therefore, in this study, the effect of guggulsterone on interleukin (IL)-1beta-induced inflammatory responses in the FLS of rheumatic patients was investigated. Treatment of FLS with IL-1beta induced production of chemokines such as RANTES and ENA-78. In addition, Western blot analysis and gelatin zymography revealed that IL-1beta activated matrix metalloproteinase (MMP)-1 and -3 in FLS. However, pre-incubation with guggulsterone completely inhibited the ability of IL-1beta to induce the production of chemokines and to activate MMPs. Although the NF-kappaB binding activity and nuclear p50 and p65 subunit levels, as well as IkappaBalpha degradation in the cytoplasm was greater in cells stimulated with IL-1beta than in unstimulated cells, treatment with guggulsterone abolished all of these increases. Collectively, these results suggest that guggulsterone would be useful as an inhibitor of joint destruction in patients with rheumatoid arthritis.
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PMID:Guggulsterone blocks IL-1beta-mediated inflammatory responses by suppressing NF-kappaB activation in fibroblast-like synoviocytes. 1849 75

To investigate if increased activation of matrix metalloproteinases (MMPs) may contribute to the large cardiovascular risk associated with obesity-related insulin resistance, we examined the effects of physiologically elevated levels of insulin and free fatty acid (FFA) on three MMPs and their physiologic inhibitors (tissue inhibitors of MMP ) in aortic tissue of male rats during euglycemic-hyperinsulinemic clamping. Hyperinsulinemia increased the active forms of MMP-2 (approximately sixfold), MMP-9 (approximately 13-fold), and membrane type 1-MMP (MT1-MMP; approximately eightfold) (all Western blots), and the gelatinolytic activity (zymography) of MMP-2 (twofold); it did not affect TIMP-1 and TIMP-2. FFA augmented the insulin-mediated increases in MMP-2 (from approximately six- to approximately 11-fold), MMP-9 (from approximately 13- to approximately 23-fold), MT1-MMP (from approximately eight- to approximately 20-fold), and MMP-2 gelatinolytic activity (from two- to threefold). FFA also increased JNK and p38 mitogen-activated protein kinase activities. The insulin- and FFA-induced hyperactivity of three proatherogenic MMPs in vascular tissues may promote degradation of extracellular matrix over time, leading to thinning of atherosclerotic capsules and acute vascular problems.
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PMID:Effects of insulin and free fatty acids on matrix metalloproteinases. 1862 23

Obesity increases the risk of developing oesophageal adenocarcinoma (OAC) as well as several other cancers. Leptin is secreted by adipocytes and serum leptin levels rise with body mass index. Leptin stimulates proliferation and inhibits apoptosis in OAC cells but the mechanisms are not fully elucidated, Transactivation of the epidermal growth factor receptor (EGFR) is an important signalling mechanism for G-protein-coupled receptors, but the relationship with leptin-type receptors has not been examined and the authors hypothesise that leptin-induced proliferation involves EGFR signalling. This study examines the effect of leptin on EGFR signalling in cultured cell lines. Leptin stimulated proliferation in four OAC lines expressing leptin receptors (OE33, OE19, BIC-1 and FLO) and this was abolished by specific EGFR inhibitors (PD153035 and AG1478). Leptin-induced proliferation was inhibited by neutralising antibodies to transforming growth factor-alpha (TGFalpha and HB-EGF) but not by anti-amphiregulin. Leptin significantly increased gene expression of HB-EGF and TGFalpha as measured by a quantitative real-time polymerase chain reaction (PCR) method but did not alter amphiregulin and EGFR gene expression. Leptin increased extracellular release of HB-EGF and TGFalpha and this was blocked by matrix metalloproteinase (MMP) inhibitors. The MMP inhibitors also abolished leptin-induced proliferation as well as leptin-induced EGFR tyrosine phosphorylation, but did not affect proliferation or EGFR activation induced by TGFalpha. The authors conclude that leptin stimulates OAC proliferation via increased gene expression of HB-EGF and TGFalpha, MMP-mediated extracellular release of HB-EGF and TGFalpha and subsequent activation of EGFR.
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PMID:Leptin stimulates the proliferation of human oesophageal adenocarcinoma cells via HB-EGF and Tgfalpha mediated transactivation of the epidermal growth factor receptor. 1898 98


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