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)

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

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

Adipose tissue and its secreted products, adipokines, have a major role in the development of obesity-associated metabolic derangements including Type 2 diabetes. Conversely, obesity and its metabolic sequelae may be counteracted by modulating metabolism and secretory functions of adipose tissue. LC-PUFAs (long-chain polyunsaturated fatty acids) of the n-3 series, namely DHA (docosahexaenoic acid; C(22:6n-3)) and EPA (eicosapentaenoic acid; C(20:5n-3)), exert numerous beneficial effects, such as improvements in lipid metabolism and prevention of obesity and diabetes, which partially result from the metabolic action of n-3 LC-PUFAs in adipose tissue. Recent studies highlight the importance of mitochondria in adipose tissue for the maintenance of systemic insulin sensitivity. For instance, both n-3 LC-PUFAs and the antidiabetic drugs TZDs (thiazolidinediones) induce mitochondrial biogenesis and beta-oxidation. The activation of this 'metabolic switch' in adipocytes leads to a decrease in adiposity. Both n-3 LC-PUFAs and TZDs ameliorate a low-grade inflammation of adipose tissue associated with obesity and induce changes in the pattern of secreted adipokines, resulting in improved systemic insulin sensitivity. In contrast with TZDs, which act as agonists of PPARgamma (peroxisome-proliferator-activated receptor-gamma) and promote differentiation of adipocytes and adipose tissue growth, n-3 LC-PUFAs affect fat cells by different mechanisms, including the transcription factors PPARalpha and PPARdelta. Some of the effects of n-3 LC-PUFAs on adipose tissue depend on their active metabolites, especially eicosanoids. Thus treatments affecting adipose tissue by multiple mechanisms, such as combining n-3 LC-PUFAs with either caloric restriction or antidiabetic/anti-obesity drugs, should be explored.
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PMID:Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. 1903 80

Dietary EPA and DHA modulate immunity and thereby may improve the aberrant immune function in obese states. To determine the effects of feeding fish oil (FO) containing EPA and DHA on splenocyte phospholipid (PL) and lipid-raft fatty acid composition, phenotypes and cytokine production, 14-week-old obese, leptin receptor-deficient JCR:LA-cp rats (cp/cp; n 10) were randomised to one of three nutritionally adequate diets for 3 weeks: control (Ctl, 0 % EPA+DHA); low FO (LFO, 0.8 % (w/w) EPA+DHA); high FO (HFO, 1.4 % (w/w) EPA+DHA). Lean JCR:LA-cp (+/ - or +/+) rats (n 5) were fed the Ctl diet. Obese Ctl rats had a higher proportion of n-3 PUFA in splenocyte PL than lean rats fed the same diet (P < 0.05). The lower n-6:n-3 PUFA ratio of splenocyte PL was consistent with the lower mitogen-stimulated interferon (IFN)-gamma and IL-1beta production by cells from obese rats (P < 0.05). Obese rats fed the FO diet had lower mitogen-stimulated Th1 (IFN-gamma) and Th2 (IL-4) cytokine responses, but IL-2 production (concanavalin A; ConA) did not differ (P < 0.05). The HFO diet was more effective in lowering IL-1beta and increasing IL-10 production (ConA, P < 0.05). This lower IL-1beta production was accompanied by a lower proportion of major histocompatability complex class II-positive cells and a higher incorporation of DHA into lipid rafts. This is the first study to demonstrate impaired responses to mitogen stimulation and altered fatty acid incorporation into the membrane PL of JCR:LA-cp rats. Feeding FO lowered the ex vivo inflammatory response, without altering IL-2 production from ConA-stimulated splenocytes which may occur independent of leptin signalling.
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PMID:Feeding long-chain n-3 polyunsaturated fatty acids to obese leptin receptor-deficient JCR:LA- cp rats modifies immune function and lipid-raft fatty acid composition. 1907 34

Visfatin is an adipokine highly expressed in visceral AT (adipose tissue) of humans and rodents, the production of which seems to be dysregulated in excessive fat accumulation and conditions of insulin resistance. EPA (eicosapentaenoic acid), an n-3 PUFA (polyunsaturated fatty acid), has been demonstrated to exert beneficial effects in obesity and insulin resistance conditions, which have been further linked to its reported ability to modulate adipokine production by adipocytes. TNF-alpha (tumour necrosis factor-alpha) is a pro-inflammatory cytokine whose production is increased in obesity and is involved in the development of insulin resistance. Control of adipokine production by some insulin-sensitizing compounds has been associated with the stimulation of AMPK (AMP-activated protein kinase). The aim of the present study was to examine in vitro the effects of EPA on visfatin production and the potential involvement of AMPK both in the absence or presence of TNF-alpha. Treatment with the pro-inflammatory cytokine TNF-alpha (1 ng/ml) did not modify visfatin gene expression and protein secretion in primary cultured rat adipocytes. However, treatment of these primary adipocytes with EPA (200 mumol/l) for 24 h significantly increased visfatin secretion (P<0.001) and mRNA gene expression (P<0.05). Moreover, the stimulatory effect of EPA on visfatin secretion was prevented by treatment with the AMPK inhibitor Compound C, but not with the PI3K (phosphoinositide 3-kinase) inhibitor LY294002. Similar results were observed in 3T3-L1 adipocytes. Moreover, EPA strongly stimulated AMPK phosphorylation alone or in combination with TNF-alpha in 3T3-L1 adipocytes and pre-adipocytes. The results of the present study suggest that the stimulatory action of EPA on visfatin production involves AMPK activation in adipocytes.
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PMID:Eicosapentaenoic acid stimulates AMP-activated protein kinase and increases visfatin secretion in cultured murine adipocytes. 1929 27

The objective of the present study was to investigate the relationship between plasma n-3 PUFA composition and weight status. A total of 124 adults, stratified by weight status: healthy weight (n 21), overweight (n 40) and obese (n 63) were recruited. Fasting blood samples, anthropometric measures and body composition were collected. Plasma fatty acid composition was determined by GC. BMI, waist circumference and hip circumference were inversely correlated with n-3 PUFA, EPA and DHA (P < 0.05 for all) in the obese group. Obese individuals had significantly lower plasma concentrations of total n-3 PUFA, compared with healthy-weight individuals (4.53 (SD 1.11) v. 5.25 (SD 1.43) %). When subjects were pooled and stratified into quartiles of total n-3 PUFA, a significant inverse trend was found for BMI (P = 0.002), waist circumference and hip circumference (P = 0.01 and P < 0.001 respectively). Higher plasma levels of total n-3 PUFA are associated with a healthier BMI, waist circumference and hip circumference. Our findings suggest that n-3 PUFA may play an important role in weight status and abdominal adiposity.
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PMID:Plasma n-3 Polyunsaturated Fatty Acids are negatively associated with obesity. 1945 27

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in development of obesity by contributing to adipogenesis, angiogenesis and extracellular matrix degradation. We have evaluated a potential functional role of TIMP-1, which inhibits most MMPs, in early stages of in vitro and in vivo adipogenesis. Overexpression of human TIMP-1 (hTIMP-1) in 3T3-F442A preadipocytes resulted in a somewhat slower differentiation into mature adipocytes, without affecting the total extent of differentiation. Local overexpression by injection of 3T3-F442A preadipocytes expressing hTIMP-1 in the back of NUDE mice kept on high fat diet (HFD) for 4 weeks, had no effect on de novo formed fat pad mass. The fat pads formed from the hTIMP-1 expressing cells did show a significantly larger blood vessel size as compared to control cells (57 + or - 4.8 microm(2) vs 38 + or - 1.4 microm(2), p=0.0017). No effect was observed on blood vessel density or on adipocyte size or density. Thus, local hTIMP-1 overexpression did not significantly affect early stages of adipogenesis as evaluated from the extent of in vitro adipocyte differentiation or of in vivo de novo adipose tissue formation.
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PMID:Effect of tissue inhibitor of matrix metalloproteinases-1 on in vitro and in vivo adipocyte differentiation. 1960 18

Adipose tissue has a key role in the development of metabolic syndrome (MS), which includes obesity, type 2 diabetes, dyslipidaemia, hypertension and other disorders. Systemic insulin resistance represents a major factor contributing to the development of MS in obesity. The resistance is precipitated by impaired adipose tissue glucose and lipid metabolism, linked to a low-grade inflammation of adipose tissue and secretion of pro-inflammatory adipokines. Development of MS could be delayed by lifestyle modifications, while both dietary and pharmacological interventions are required for the successful therapy of MS. The n-3 long-chain (LC) PUFA, EPA and DHA, which are abundant in marine fish, act as hypolipidaemic factors, reduce cardiac events and decrease the progression of atherosclerosis. Thus, n-3 LC PUFA represent healthy constituents of diets for patients with MS. In rodents n-3 LC PUFA prevent the development of obesity and impaired glucose tolerance. The effects of n-3 LC PUFA are mediated transcriptionally by AMP-activated protein kinase and by other mechanisms. n-3 LC PUFA activate a metabolic switch toward lipid catabolism and suppression of lipogenesis, i.e. in the liver, adipose tissue and small intestine. This metabolic switch improves dyslipidaemia and reduces ectopic deposition of lipids, resulting in improved insulin signalling. Despite a relatively low accumulation of n-3 LC PUFA in adipose tissue lipids, adipose tissue is specifically linked to the beneficial effects of n-3 LC PUFA, as indicated by (1) the prevention of adipose tissue hyperplasia and hypertrophy, (2) the induction of mitochondrial biogenesis in adipocytes, (3) the induction of adiponectin and (4) the amelioration of adipose tissue inflammation by n-3 LC PUFA.
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PMID:n-3 PUFA: bioavailability and modulation of adipose tissue function. 1969 99

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in the development of obesity by contributing to adipogenesis, angiogenesis, and extracellular matrix degradation. We have evaluated a potential functional role of TIMP-1, which inhibits most MMPs, in in vivo adipogenesis. Therefore, human (h) TIMP-1 was overexpressed by injection in the tail vein of NUDE mice of an adenoviral vector 3 days before injection of 3T3-F442A preadipocytes in the back. After 4 weeks of high-fat diet, the de novo formed fat was analyzed. Overexpression of hTIMP-1 had no effect on de novo formed fat pad mass. However, the blood vessel density of the fat pads from mice overexpressing hTIMP-1 was significantly lower than in controls (587 +/- 11 mm(-2) vs. 806 +/- 20 mm(-2), P < 0.0001) whereas the adipocytes were somewhat larger (1,477 +/- 44 microm(2) vs. 1,285 +/- 32 microm(2), P = 0.03). Thus, in vivo hTIMP-1 overexpression did not significantly affect the extent of de novo adipose tissue formation, but was associated with significantly lower blood vessel density.
Obesity (Silver Spring) 2010 Mar
PMID:Blood vessel density in de novo formed adipose tissue is decreased upon overexpression of TIMP-1. 1973 Apr 23

Based on mechanistic and epidemiological data, we raise the question of the relationship between qualitative dietary polyunsaturated fatty acids (PUFA) changes and increase in obesity. In this double-blind trial, we studied the effects on 160 overweight volunteers (body mass index, BMI >30) of a 90 days experimental diet rich principally in animal fat with a low PUFA/saturated fatty acid (SFA) ratio but a low n-6/n-3 ratio, using animal products obtained from linseed-fed animals. The control diet provided less animal fat, a higher PUFA/SFA ratio and a higher n-6/n-3 ratio. Both diets excluded seafood. In the experimental group, we observed a significant increase in red blood cell (RBC) alpha-linolenic acid content and a slight increase in EPA and DHA derivatives, while in the control group we observed a significant reduction in EPA and DHA content. Between groups now, the difference in the three n-3 fatty acids changes in RBC was significant. This demonstrates that plasma EPA and DHA levels can be maintained without fish if products from linseed-fed animals are used. During the diets, we noted a significant reduction in weight, BMI and hip circumference within both groups of volunteers. However, no significant difference was observed between the control group and the experimental group. Interestingly, 150 days after the end of the trial (i.e., day 240), we noted a significant weight gain in the control group, whereas no significant weight gain was observed in the experimental group. This was also observed for the BMI and hip circumference. Moreover, significant differences in BMI (P < 0.05) and weight (P = 0.05) appeared between the two groups, showing in both cases a smaller increase in the experimental group. During the 90 days trial, we did not observe any differences between groups in terms of total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides, suggesting that the saturate content and the P/S ratio are not as important as the n-6 and n-3 fatty acid composition.
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PMID:The consumption of food products from linseed-fed animals maintains erythrocyte omega-3 fatty acids in obese humans. 2001 23


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