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)

Our objective was to investigate expression of A disintegrin and metalloproteinase (ADAM) and ADAM proteins with a thrombospondin (TS) motif (ADAMTS) family members in adipose tissue of lean and obese mice. Five-week-old male mice were kept on standard chow (SFD) or on high fat diet (HFD) for 15 weeks, and subcutaneous (SC) and gonadal (GON) adipose tissue, as well as mature adipocytes and stromal-vascular (S-V) cells were harvested. mRNA levels of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-alpha (TNF-alpha), ADAM-17 (TACE or TNF-alpha converting enzyme), ADAMTS-1 and ADAMTS-8 were quantified in isolated adipose tissues and cell fractions, and during differentiation of murine preadipocytes. The HFD resulted in a significantly enhanced weight of isolated SC and GON fat pads, and in enhanced blood levels of glucose, cholesterol and PAI-1. ADAM-17, TNF-alpha, PAI-1, ADAMTS-1 and ADAMTS-8 mRNA were detected in both SC and GON adipose tissue of lean mice (SFD). In SC adipose tissue of obese mice (HFD), the expression of ADAM-17 and PAI-1 was enhanced and that of ADAMTS-1 reduced, whereas in GON adipose tissue expression of TNF-alpha was enhanced and that of ADAMTS-8 reduced. In lean and obese mice, expression of ADAM-17, ADAMTS-1 and ADAMTS-8 was higher in the S-V cell fraction than in mature adipocytes. During differentiation of murine 3T3-F442A preadipocytes, expression of ADAM-17 and ADAMTS-1 remained virtually unaltered, whereas that of ADAMTS-8 decreased as adipocytes matured. Several ADAM and ADAMTS family members are expressed in adipose tissue and during differentiation of preadipocytes. Modulation of their expression upon development of obesity is adipose tissue-dependent.
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PMID:Differential expression of plasminogen activator inhibitor-1, tumor necrosis factor-alpha, TNF-alpha converting enzyme and ADAMTS family members in murine fat territories. 1252 24

Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling, a process that takes place during obesity-mediated adipose tissue formation. Here, we examine expression profiles and the potential role of MMPs and their tissue inhibitors (TIMPs) in adipose tissue remodeling during obesity. Expression patterns are studied by Northern blot and real-time PCR in two genetic models of obesity (ob/ob and db/db mice) and in a diet-induced model of obesity (AKR mice). Of the MMPs and TIMPs studied, mRNA levels for MMP-2, MMP-3, MMP-12, MMP-14, MMP-19, and TIMP-1 are strongly induced in obese adipose tissues compared with lean tissues. In contrast, MMP-7 and TIMP-3 mRNAs are markedly decreased in obesity. Interestingly, enzymatic activities of MMP-12 and of a new identified adipocyte-derived 30-kDa metalloproteinase are enhanced in obese adipose tissue fractions, demonstrating that MMP/TIMP balance is shifted toward increased matrix degradation in obesity. Finally, we analyze the modulation of MMP-2, MMP-19, and TIMP-1 during 3T3-L1 preadipocyte differentiation, and we explore the effect of inhibition of MMP activity on in vitro adipogenesis. We find that the synthetic MMP inhibitor BB-94 (Batimastat) decreases adipose conversion of 3T3-L1 and primary rat preadipocytes. BB-94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of CCAAT/enhancer-binding protein beta, a transcription factor that is thought to play a major role in the adipogenic program. Such findings support a role for the MMP/TIMP system in the control of proteolytic events and adipogenesis during obesity-mediated fat mass development.
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PMID:Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. 1252 76

Matrix metalloproteinase 19 (MMP-19) is a member of the MMP family of endopeptidases that, in contrast to most MMPs, is widely expressed in human tissues under normal quiescent conditions. MMP-19 has been found to be associated with ovulation and angiogenic processes and is deregulated in diverse pathological conditions such as rheumatoid arthritis and cancer. To gain further insights into the in vivo functions of this protease, we have generated mutant mice deficient in Mmp19. These mice are viable and fertile and do not display any obvious abnormalities. However, Mmp19-null mice develop a diet-induced obesity due to adipocyte hypertrophy and exhibit decreased susceptibility to skin tumors induced by chemical carcinogens. Based on these results, we suggest that this enzyme plays an in vivo role in some of the tissue remodeling events associated with adipogenesis, as well as in pathological processes such as tumor progression.
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PMID:Diet-induced obesity and reduced skin cancer susceptibility in matrix metalloproteinase 19-deficient mice. 1516 94

Tissue inhibitor of metalloproteinase (TIMP)-1 is an adipocyte-secreted protein upregulated in obesity which promotes adipose tissue development. Furthermore, the proinflammatory adipocytokines tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-6 induce insulin resistance, and plasma concentrations are increased during weight gain. In the current study, the impact of TNFalpha and IL-6 on TIMP-1 mRNA and protein expression was determined in 3T3-L1 adipocytes. Interestingly, TNFalpha and IL-6 induced TIMP-1 protein secretion more than 3- and 2-fold, respectively. Furthermore, TIMP-1 mRNA was upregulated in a time- and dose-dependent fashion. Inhibitor experiments suggested that nuclear factor kappaB and p 44/42 mitogen-activated protein kinase are involved in both, basal and adipocytokine-induced TIMP-1 expression. Moreover, the thiazolidinedione troglitazone partly reversed TNFalpha- but not IL-6-induced TIMP-1 synthesis. Taken together, we demonstrate that TIMP-1 expression is selectively upregulated in fat cells by proinflammatory adipocytokines and might play a role in maintaining adipose tissue mass in obesity.
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PMID:Proinflammatory adipocytokines induce TIMP-1 expression in 3T3-L1 adipocytes. 1628 49

Tissue inhibitor of metalloproteinase (TIMP)-1 is an adipocytokine upregulated in obesity which might promote adipose tissue development. In the current study, the impact of the beta-adrenergic agonist isoproterenol on TIMP-1 gene expression and secretion was determined in 3T3-L1 adipocytes. Interestingly, isoproterenol increased TIMP-1 secretion 2.7-fold. Furthermore, isoproterenol induced TIMP-1 mRNA in a time- and dose-dependent fashion with significant effects observed as early as 1 h after effector addition and at concentrations as low as 1 microM isoproterenol. Significant isoproterenol-induced upregulation of TIMP-1 mRNA could also be found in immortalized brown adipocytes. Inhibitor experiments confirmed that the positive effect of isoproterenol on TIMP-1 is mediated via beta-adrenergic receptors and protein kinase A. Moreover, increasing cAMP levels with forskolin or dibutyryl-cAMP was sufficient to stimulate TIMP-1 synthesis. Insulin induced basal TIMP-1 mRNA, but did not significantly influence forskolin-induced TIMP-1 expression. Taken together, we demonstrate that TIMP-1 expression and secretion are selectively upregulated in adipocytes by beta-adrenergic agonists via a classic Gs-protein-coupled pathway.
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PMID:Tissue inhibitor of metalloproteinase 1 expression and secretion are induced by beta-adrenergic stimulation in 3T3-L1 adipocytes. 1673 96

The adipokine tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated when weight is gained and promotes adipose tissue development. In the present study, the effect of insulin resistance-inducing and proinflammatory interleukin (IL)-1 beta on TIMP-1 gene expression and secretion was investigated in 3T3-L1 adipocytes. Interestingly, protein secretion and mRNA production of TIMP-1 were significantly stimulated by IL-1 beta. Thus, IL-1 beta induced TIMP-1 secretion in a dose-dependent manner with maximal 3.5-fold upregulation seen at 0.67 ng/ml IL-1 beta relative to untreated cells. Furthermore, TIMP-1 mRNA synthesis was significantly stimulated by IL-1 beta in a dose-dependent fashion with 2.5-fold induction seen at IL-1 beta concentrations as low as 0.02 ng/ml and maximal 8.1-fold upregulation found at 20 ng/ml effector. Induction of TIMP-1 mRNA was also time dependent with maximal 9.6-fold upregulation detectable after 8 h of IL-1 beta treatment. Signaling studies suggested that janus kinase 2 is involved in IL-1 beta-induced TIMP-1 mRNA expression. Taken together, our results demonstrate that the TIMP-1 expression is selectively upregulated by proinflammatory IL-1 beta, supporting a direct association between insulin resistance, inflammation, and adipose tissue development in obesity.
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PMID:Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1 beta in 3T3-L1 adipocytes. 1857 71

Extracellular matrix (ECM) and ECM-hydrolytic enzymes play critical roles in reproduction, development, morphogenesis, wound healing, tissue repair, regeneration, and remodeling. They are also involved in pathological processes such as inflammation, arthritis, cardiovascular diseases, stroke, neurodegeneration, metabolic syndrome, and cancer invasion and metastasis. Other reviews summarized the structure and function of ECM-degrading enzymes in cancer and other diseases. This review will focus on current insights of major protease families and other digestive enzymes that play significant roles in ECM remodeling and ECM-related pathologies. For example, the functions of matrix metalloproteinases in modulating adipogenesis, and their subsequent implications in obese patients, are discussed. Recent discovery and characterization of nineteen members of the human disintegrin-metalloproteinase with thrombospondin motif family have revealed new opportunities of investigating these enzymes in human pathologies, especially in the pathogenesis of osteoarthritis. Although kallikrein-3 was discovered many years ago as prostate specific antigen, the biomarker for detecting human prostate cancer and monitoring its recurrence in patients after surgery, fifteen members of the kallikrein family were reported to participate in physiological and pathological processes. Furthermore, exciting research has been carried out on other important ECM-digestive enzymes, including heparanase, cathepsins, hyaluronidases, and matriptases. Research data have suggested that these enzymes are potential therapeutic targets and biomarkers for cancer, arthritis, obesity, diabetic complications, multiple sclerosis, cardiovascular diseases, cerebral vascular diseases, and many other pathological conditions.
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PMID:A fresh prospect of extracellular matrix hydrolytic enzymes and their substrates. 1935 69

Osteoarthritis (OA) is the most common form of arthritis worldwide. In this condition, damage to the extracellular matrix (ECM) of cartilage occurs, resulting in joint destruction. Factors mediating cartilage damage include mechanical injury, cytokine and superoxide release on a background of genetic susceptibility and obesity. Studies of arthritic cartilage show increased production of ECM molecules including type II collagen, cartilage oligomeric matrix protein, fibronectin (FN) and fibromodulin. Recent reports suggest that ECM proteins may become endogenous catabolic factors during joint damage. Activation of pro-inflammatory pathways by ECM proteins has led to their description as damage-associated molecular patterns (DAMPs). The ECM proteins involved include fibromodulin, which activates the complement pathway and may promote the persistence of joint inflammation. Fragmentation of type II collagen, FN and hyaluronan reveals cryptic epitopes that stimulate proteolytic enzymes including matrix metalloproteinases and aggrecanases (ADAMTSs - a disintegrin and metalloproteinase with thrombospondin type 1 motifs). Proteolytic fragments also stimulate the release of nitric oxide, chemokines and cytokines and activation of the MAP kinases. Reports are emerging that the receptors for the fragments described involve interaction with integrins and toll-like receptors. In this review the contribution of endogenous ECM molecules to joint destruction will be discussed. A deeper understanding of the pathways stimulated by endogenous ligands could offer potential avenues for novel therapies in the future.
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PMID:Analysing the role of endogenous matrix molecules in the development of osteoarthritis. 1976 1

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized as a type I transmembrane protein, which is proteolytically cleaved to release a soluble form via members of the a disintegrin and metalloproteinase (ADAM) family of proteolytic enzymes. This study was designed to elucidate the molecular mechanism underlying insulin-induced HB-EGF shedding in adipocytes in vitro. The 3T3-L1 adipocytes with stable expression of alkaline phosphatase (AP)-tagged proHB-EGF (3T3-L1/HB-EGF-AP adipocytes) were developed and AP activities of conditioned media were determined. Using 3T3-L1/HB-EGF-AP adipocytes, we demonstrated that insulin induces HB-EGF shedding in differentiated 3T3-L1 adipocytes in a dose- and time-dependent manner. There is no significant increase in insulin-induced HB-EGF shedding in undifferentiated 3T3-L1 preadipocytes. Studies with metalloprotease inhibitors suggested that insulin-induced HB-EGF shedding in adipocytes is mediated at least in part via ADAM17. Treatment with recombinant HB-EGF results in a dose- and time-dependent increase in HB-EGF shedding in adipocytes, which is significantly suppressed by pharmacologic blockade of ADAM17 (P < 0.01). Moreover, insulin-induced HB-EGF shedding in adipocytes is significantly inhibited by AG1478, an EGF receptor antagonist (P < 0.01). This study provides in vitro evidence that insulin induces HB-EGF shedding in 3T3-L1 adipocytes. Our data also suggest the role of ADAM17 in insulin-induced HB-EGF shedding in adipocytes.
Obesity (Silver Spring) 2010 Oct
PMID:Insulin-induced ectodomain shedding of heparin-binding epidermal growth factor-like growth factor in adipocytes in vitro. 2011 Oct 15

Adipokines play key roles in the regulation of bone growth, obesity, diabetes mellitus type 2, and HIV infection. As a newly discovered hormone in the adipokine family, the precise role of apelin on articular cartilage metabolism is not yet clear. The aim of this study was to evaluate the role of apelin on articular cartilage. In vitro, we examined the effects of apelin on normal chondrocyte proliferation and gene expression of metalloproteinases (MMPs) and interleukin-1beta (IL-1beta). In vivo, by intra-articular injection with apelin, we examined MMP-3, -9, collagen II and IL-1beta at both gene and protein levels. Furthermore, we measured the messenger RNA (mRNA) expression of ADAMTS-4 and -5 (a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5) and the proteoglycan content in articular cartilage. Apelin stimulated the proliferation of chondrocytes and significantly increased mRNA levels of MMP-1, -3, -9 and IL-1beta in vitro. Intra-articular injection with apelin in vivo up-regulated the expression of MMP-3, -9, and IL-1beta as well as decreased the level of collagen II. Additionally, after treatment with apelin, mRNA levels of ADAMTS-4 and -5 markedly increased and depletion of proteoglycan in articular cartilage was found by histological assessment. These findings suggest that apelin plays a catabolic role in cartilage metabolism and is a risk factor in the pathophysiology of osteoarthritis.
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PMID:Apelin plays a catabolic role on articular cartilage: in vivo and in vitro studies. 2066 51


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