Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of recombinant human tumor necrosis factor (TNF) on the capillary growth was evaluated using an in vitro angiogenesis model recently developed. Sprague-Dawley rat microvessel fragments, from epididymal fat pads, seeded onto the confluent culture of myofibroblastic cells from the same tissue origin, gave rise to microvascular networks on and in the multilayered myofibroblastic cells. In contrast, the capillary growth from the vessel fragments was markedly inhibited in the presence of 10-1,000 U TNF/ml. Monoclonal antibody against TNF completely neutralized the capillary growth inhibitory activity of TNF. The mode of angiogenesis inhibitory action of TNF was also examined by use of bovine capillary endothelial (BCE) cells and rat myofibroblastic cells. TNF exerted growth inhibitory and cytotoxic actions against BCE cells cultivated on the various basement membrane components, such as extracellular matrix secreted by BCE cells, fibronectin, laminin, and type IV collagen. An irreversible damage to most of the BCE cells was observed ultrastructurally after 60 hours' exposure to TNF. TNF, however, did not injure the myofibroblastic cells but rather stimulated their growth. These findings indicate that TNF inhibits in vitro capillary growth by its direct cytostatic and cytotoxic actions to microvascular endothelial cells.
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PMID:Tumor necrosis factor inhibiting angiogenesis in vitro. 244 19

In primary cultures of rat preadipocytes (PA) isolated from epididymal or perirenal depots, rat serum is more effective than other animal sera (fetal calf, newborn calf, human, horse, rabbit, cat, sheep, goat, dog, pig) in promoting adipogenic conversion, biochemical differentiation, and mitogenesis. Only mouse serum is comparable to rat serum. This activity is attributable to a specific growth factor (preadipocyte stimulating factor, PSF). An assay for PSF in rat serum was devised using PA from perirenal fat of 3-month-old Fischer 344 rats grown first to confluence in FCS for 8 days and then for the next 3 days in test serum, followed by measurement of triglyceride (TG) and glycerol-3-phosphate dehydrogenase (GPDH). Rat serum induces dose-dependent rapid cell division, which coincides with accumulation of TG and increase of GPDH; for routine quantitation, TG is assayed. The biochemical characteristics of PSF in serum are as follows: stable at 4 degrees C for up to 1 year; inactivated at 100 degrees C (80% loss, 30 min) but stable at 56 degrees C for 1 hr; stable at pH 2-12; non-dialyzable; completely resistant to pepsin, trypsin, and chymotrypsin but destroyed by pronase and subtilisn; stable to DTT and periodate; and m.w. between 68 kDa (Sephacryl-300) and 58 kDa (Sephacryl-300 in 5 M urea). PSF activity is greater in serum from Wistar than from Fischer 344 rats, while activity of serum from Zucker obese (fa/fa) rats is at least as great as that from Wistar rats and, like serum of rats made obese by feeding a high-fat, high-carbohydrate diet, is not suppressed. PSF activity is not due to insulin, insulin-like growth factor-1 (IGF-1), growth hormone, glucocorticoids, or combinations of these hormones. PSF activity was not seen with a number of growth factors including colony-stimulating factor (CSF-1), GM-CSF, interleukins 1, 2, and 3, neuroleukin, tumor necrosis factor, and others. PSF is distinct from the low molecular weight (4-8 kDa) differentiation factor present in rat serum, FCS, and human serum that promotes the adipogenic conversion and cellular differentiation of 3T3-L1, 3T3-F442A, and Ob17 cells. PSF appears to be a new differentiation factor for rat preadipocytes, has properties suggestive of a highly glycosylated protein, and may be highly species specific.
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PMID:Preadipocyte stimulating factor in rat serum: evidence for a discrete 63 kDa protein that promotes cell differentiation of rat preadipocytes in primary cultures. 268 98

When added to murine adipocytes in culture, tumor necrosis factor (TNF) decreases the levels of lipoprotein lipase (LPL). Semb et al (1987. J. Biol Chem. 262: 8390-8394) have shown that administration of murine TNF to rats decreases lipoprotein lipase (LPL) in the epididymal fat pad with maximal inhibition requiring several hours. We have now tested the effects of treatment of rats with TNF on LPL activity in a variety of tissues and find that few show decreases in LPL under conditions that acutely increase serum triglycerides. Ninety minutes after treatment of male rats with human TNF (25 micrograms/200 g, i.v.), serum triglycerides rose 2.2-fold but there was no decrease in LPL activity in epididymal fat. Sixteen hours after TNF treatment LPL activity had decreased by 44% in epididymal fat, consistent with the previously reported data. In contrast, in female rats, no significant decrease was seen in LPL activity in parametrial adipose tissue at either 90 min or 16 hr after TNF administration despite increases in serum triglycerides (1.8-fold and 1.5-fold, respectively). There was little change in LPL activity in most other adipose tissue sites of male or female rats at either time after TNF treatment. No effect of TNF was seen on heart or diaphragm muscle LPL at any time. TNF treatment of both male and female rats produces consistent increases in de novo hepatic lipogenesis in vivo under conditions that increase serum triglycerides. It is unlikely that the limited effects of TNF on LPL in vivo can account for the rapid and sustained increase in serum triglycerides.
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PMID:Effect of tumor necrosis factor administration in vivo on lipoprotein lipase activity in various tissues of the rat. 275 38

Levels of mRNA for lipoprotein lipase (LPL) in guinea pig epididymal adipose tissue, heart and liver were determined by dot blot analysis of total RNA using a cDNA probe complementary to the coding region, and compared to the LPL activity. For adipose tissue we also measured the incorporation of radioactivity into immunoprecipitable LPL after pulse-labeling with [35S]methionine. LPL activity was 93%, LPL mRNA 82% and LPL synthesis 85% lower in epididymal fat pads from animals fasted for 48 h compared to rigorously fed animals. In contrast, neither LPL activity nor LPL mRNA levels differed in heart. A single dose of tumor necrosis factor (TNF) decreased LPL activity and LPL mRNA in fat pads with no effects in heart. In the liver, TNF caused a marked increase in LPL mRNA levels, which are normally very low. Northern-blot analysis confirmed a previous observation that the patterns of mRNA species differ between heart, in which a 3.8-kb mRNA dominates, and adipose tissue, in which the LPL mRNAs of 3.3 and 2.1 kb occur in similar abundance as the 3.8-kb species.
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PMID:Tissue-specific regulation of guinea pig lipoprotein lipase; effects of nutritional state and of tumor necrosis factor on mRNA levels in adipose tissue, heart and liver. 339 78

To investigate the effects of cytokines on adipocyte lipolysis, a macrophage cell line (RAW 264.7) was treated with Escherichia coli lipopolysaccharide (1 microgram/ml) for 18 h to induce cytokine release. Conditioned medium (5%, vol/vol) from these cells was added to rat epididymal adipocytes isolated and incubated under sterile conditions. After incubation, the adipocytes were washed, and the rate of lipolysis (glycerol release) was determined after a further 1-h incubation. The conditioned medium caused an approximately 2.7-fold increase in lipolysis, detectable after 6-12 h, maximal by 24 h, and reversible by 48 h after washing the cells. The effect of conditioned medium was reversed by a neutralizing antibody to mouse tumor necrosis factor-alpha (TNF alpha), and the direct addition of recombinant human TNF alpha (0.1-50 ng/ml) reproduced the effect, with a half-maximally effective concentration of approximately 3 ng/ml. The effect of TNF on the expression of hormone-sensitive lipase (HSL; the rate-limiting enzyme for lipolysis) was investigated by Western immunoblots using an antibody raised to a bacterially expressed 96-amino acid portion of the HSL enzyme. TNF treatment did not alter the concentration of immunoreactive HSL. From these data we conclude that 1) macrophages release a cytokine(s) in response to lipopolysaccharide that stimulates lipolysis in freshly isolated adipocytes; 2) TNF alpha can account for most, or perhaps all, of this effect; 3) TNF alpha increases the rate of lipolysis by a mechanism that does not involve increased expression of HSL. Based on the time-dependent aspects of TNF alpha stimulation and the lack of change in immunoreactive HSL, the findings suggest a TNF-induced posttranslational modification of the enzyme.
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PMID:Tumor necrosis factor increases the rate of lipolysis in primary cultures of adipocytes without altering levels of hormone-sensitive lipase. 819 85

The effects of multicytokine inducer, OK-432, on tumor-induced metabolic alterations were studied by assessing three key regulatory enzymes of gluconeogenesis, de novo fatty acid synthesis and the triglyceride clearance pathways. Two Klinish Einheit (KE) of OK-432 was subcutaneously injected on alternate days, for 10 days, into Fischer 344 rats with or without methylcholanthrene-induced sarcoma. At the time of sacrifice, the tumors accounted for approximately 23% of their total body weight. The injections of OK-432 did not affect the amount of food intake in either the tumor bearers or the controls. The tissue lipoprotein lipase activities in the epididymal fat pads of the tumor bearers were significantly decreased compared with the controls (P < 0.01). Phosphoenolpyruvate carboxykinase activity in the liver was significantly increased (P < 0.01), while malic enzyme activity tended to be decreased in the tumor bearers compared with the controls. However, there were no significant differences in those activities depending on the OK-432 injections, even though OK-432 induced tumor necrosis factor (TNF) and increased cytotoxic activities in the mesenteric lymph nodes as well as in the spleen. Thus, although the role of monokines in inducing cancer cachexia is not yet clearly understood, OK-432 was not able to revert the tumor-induced metabolic alterations which lead to tissue wasting and cancer cachexia.
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PMID:The effects of a biological response modifier, OK-432, on tumor-induced alterations in the host metabolism. 836 14

Because tumor necrosis factor (TNF) inhibits adipose cell differentiation in vitro and affects lipid metabolism in vivo, we treated adult or newborn rats for 1 wk with daily intraperitoneal injections (100 U/g of body weight) or continuous intraperitoneal diffusion (3500 U/h) of human recombinant TNF. Three weeks after the end of treatment, the long-term effect of the cytokine was examined on adipose tissue development. Control and TNF-injected rats did not differ in growth or development of perirenal, retroperitoneal and epididymal adipose tissues. Nevertheless, the size distribution of epididymal adipocytes of adult injected rats presented a slight shift towards larger values in the cytokine group. When TNF was administered chronically, the cytokine exerted an anorectic effect, which was alleviated after the end of treatment. The weights of the excised adipose tissues were depressed (P < .025) by TNF administration. Part of this effect was due to the induced anorexia. The size distributions of the epididymal adipocytes of pair-fed and TNF-treated rats were both shifted to smaller (P < 0.01) values than for the controls. The ratio of triglycerides over total lipids was, however, reduced by TNF specifically, but only at the retroperitoneal (P < .05) and not the epididymal site. These results indicate that in contrast to acute treatment, chronic TNF treatment slightly inhibited adipose tissue development in vivo; however, most of this effect was attributable to the associated anorexia.
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PMID:Effects of acute or chronic administration of tumor necrosis factor on rat adipose tissue development. 892 89

High levels of adipose tissue-derived tumor necrosis factor-alpha (AT-TNF) mRNA and protein have previously been associated with genetic models of obesity and insulin resistance. Because there are endogenous TNF inhibitors it is unknown if AT-TNF activity is also increased. We hypothesized that AT-TNF activity would increase in older animals because of an accumulation of fat mass. We chose to study 2 different-aged male Fischer 344 rats, 3-month-old (young) and 14-month-old (mature) because fat mass should be quite different but insulin action on glucose metabolism similar. Indeed, mature rats had over 1.5-fold more fat mass, but whole body insulin resistance, as estimated by fasting plasma insulin, was similar to young rats. Mature rats had twice as much AT-TNF activity as the young in both the epididymal (EPI) and retroperitoneal (Retro) fat pads (p < .0005). AT-TNF correlated with fasting plasma insulin in Retro only (r = .48, p = .04). AT-TNF activity strongly correlated with cell size in both EPI and Retro (r = .79 and .81, respectively, p < .0001). Because cytokines can be regulated at several levels, AT-TNF activity, protein, and mRNA were measured. AT-TNF protein levels were higher in young rats, suggesting that these animals may secrete an inhibitor that reduces AT-TNF activity. There were no significant differences in AT-TNF mRNA between groups. Since TNF has been shown to affect several key genes in tissue culture, mRNA for lipoprotein lipase, hormone-sensitive lipase, and Glut4 were measured. No differences were found between groups. In summary, AT-TNF activity increased in mature animals in relation to adipose cell size.
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PMID:Adipose tissue-derived tumor necrosis factor-alpha activity is elevated in older rats. 922 23

To address the hypothesis that tumor necrosis factor (TNF)-alpha has a role in obesity-associated insulin resistance or the regulation of in vivo lipid metabolism, mice with targeted disruption of the TNF-alpha gene were generated and studied. The absence of TNF-alpha protein in TNF-null (-/-) mice was confirmed. Lean or obese (gold-thioglucose [GTG]-injected) homozygous (-/-) mice were compared with lean or obese age- and sex-matched wild-type (+/+) mice derived from the same line at 13, 19, and 28 weeks of age. The following parameters were significantly affected in lean -/- versus +/+ mice: Body weight was not affected until week 28 (decreased by 14%); epididymal fat pad weight also decreased (25%) at this time, as did percentage body fat (16%), while percentage body protein was increased 13%. Fed plasma insulin levels decreased 47% (28 weeks), triglyceride levels decreased (all three ages; maximum 35% at 19 weeks), and fed plasma leptin decreased 33% (28 weeks). Fasting glucose was slightly (10%) reduced, but the glucose response to an oral glucose tolerance test (OGTT) was not affected. There was a trend (NS) toward increased total adipose tissue lipoprotein lipase in -/- versus +/+ mice. GTG-treatment resulted in obese -/- and +/+ mice with equal mean body weights (42 and 58% increased weight versus lean mice). The following parameters were significantly different in obese -/- mice: fasting plasma glucose decreased 13% (28 weeks), fed plasma insulin decreased 67% (28 weeks), and insulin response to OGTT was decreased by 50%. For both groups of obese mice, glucose levels during the OGTT were substantially increased compared with those in lean mice; however, mean stimulated glucose levels were 20% lower in obese -/- versus +/+ mice. We conclude 1) that TNF-alpha functions to regulate plasma triglycerides and body adiposity and 2) that although TNF-alpha contributes to reduced insulin sensitivity in older or obese mice, the absence of TNF-alpha is not sufficient to substantially protect against insulin resistance in the GTG hyperphagic model of rodent obesity.
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PMID:Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. 928 59

Adipose tissue-derived tumor necrosis factor-alpha (AT-TNF) has been associated with genetic models of insulin resistance and obesity. It is presently unknown if secreted AT-TNF protein is bioactive or whether it can be increased by environmentally induced obesity. In this study, male Wistar rats were fed either a low fat (LF; 12% of energy from corn oil) or a high fat (HF; 45% of energy from corn oil) diet for 5 weeks. From previous data, it is known that after 3 weeks, HF fed animals are obese and insulin resistant compared with the LF group. Hence, animals were killed at 1 week of HF feeding, during the acute response to the diet, and at 5 weeks, when differences in body fat are manifest. Weight gain was significantly increased by diet (P = 0.03) and time (P < 0.0001). AT-TNF bioactivity was measured on secreted protein collected from medium of minced, incubated epididymal (EPI), mesenteric (MES), and retroperitoneal (RETRO) fat pads. AT-TNF bioactivity was significantly increased by diet (P = 0.003) in the RETRO pad and tended to increase (P = 0.07) in EPI. AT-TNF activity was unaffected by diet or time in the MES pad. In the RETRO pad, TNF activity correlated negatively with RETRO fat cell number (r = -0.46, P = 0.002). Secreted AT-TNF protein did not correlate with AT-TNF activity but instead decreased in RETRO with time but not diet. In EPI, secreted AT-TNF protein decreased with the HF diet. Thus, these data suggest that high fat diets and obesity can influence AT-TNF bioactivity and secretion but in an apparent fat pad-specific manner.
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PMID:High fat diets elevate adipose tissue-derived tumor necrosis factor-alpha activity. 934 92


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