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)

Pioglitazone, a thiazolidinedione, is a novel antidiabetic compound that can lower blood glucose in diabetic rodents by increasing insulin sensitivity in target tissues. We have previously demonstrated that pioglitazone can enhance the insulin- or insulin-like growth factor-1-regulated differentiation of 3T3-L1 cells, a cell line that undergoes morphological and biochemical differentiation to mature adipocytes [Mol. Pharmacol. 41:393-398 (1992)]. In this study, we have examined the effect of pioglitazone on the expression of the adipocyte fatty acid-binding protein (aFABP) in ob/ob mice and 3T3-L1 cells. Administration of the drug to mice was observed to cause a dose-dependent increase in aFABP mRNA expression in epididymal fat, which was correlated with a decrease in blood glucose and insulin levels. Treatment of 3T3-L1 cells with pioglitazone enhanced aFABP expression in a time-dependent fashion. To explore a possible direct effect of pioglitazone on aFABP expression, a chimeric gene was constructed containing the aFABP promoter fused upstream of the bacterial reporter gene for chloramphenicol acetyltransferase. After transfection into 3T3-L1 cells and selection of stable transformants, regulation of the chimeric gene was studied. Pioglitazone, in combination with insulin or insulin-like growth factor-1, was observed to elicit a dose-dependent increase in expression, indicating a role for pioglitazone in regulating transcription of the aFABP gene. Several thiazolidinedione analogs were tested for their ability to induce the expression of the chimeric gene, and it was found that activity in this assay paralleled the structure-activity relationships observed for enhancement of 3T3-L1 cell differentiation. These observations on control of aFABP gene expression by pioglitazone suggest possible mechanisms by which cellular sensitivity to insulin may be regulated.
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PMID:Adipocyte fatty acid-binding protein: regulation of gene expression in vivo and in vitro by an insulin-sensitizing agent. 143 36

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

Stromal-vascular cells from the epididymal fat pad of 4-week-old rats, when cultured in a medium containing insulin or insulin-like growth factor, IGF-I, triiodothyronine and transferrin, were able to undergo adipose conversion. Over ninety percent of the cells accumulated lipid droplets and this proportion was reduced in serum-supplemented medium. The adipose conversion was assessed by the development of lipoprotein lipase (LPL) and glycerol-3-phosphate dehydrogenase (GPDH) activities, [14C]glucose incorporation into polar and neutral lipids, triacylglycerol accumulation and lipolysis in response to isoproterenol. Similar results were obtained with stromal-vascular cells from rat subcutaneous and retroperitoneal adipose tissues. Stromal-vascular cells required no adipogenic factors in addition to the components of the serum-free medium. Insulin was required within a physiological range of concentrations for the emergence of LPL and at higher concentrations for that of GPDH. When present at concentrations ranging from 2 to 50 nM, IGF-I was able to replace insulin for the expression of both LPL and GPDH. The development of a serum-free, chemically defined medium for the differentiation of diploid adipose precursor cells opens up the possibility of characterizing inhibitors or activators of the adipose conversion process.
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PMID:Development of a chemically defined serum-free medium for differentiation of rat adipose precursor cells. 353 40

A peptide with insulin-like activity was isolated from human plasma. In the purification, insulin-like activity (ILA) was monitored by radioreceptor assay for insulin, using human placental membrane and [125I]-insulin. ILA was extracted from Cohn fraction III with acid-ethanol and chromatographed on Sephadex G-75 in 1% formic acid. When the active fractions were subjected to ion-exchange chromatography with CM-cellulose, the ILA was adsorbed to the column at pH 5.0 and was eluted with a gradient of ammonium acetate. The chromatographic behavior of the ILA was not identical to that of somatomedin A as determined by radioreceptor assay (RRA) for the latter. On isoelectric focusing of the ILA from the CM-cellulose column, insulin-like activity was distributed over a wide pH range. The ILA that was focused at pH 7.5-9.0 was further purified by gel filtration on Sephadex G-50 in 1 M acetic acid. The specific activity of the basic ILA was approximately 200 mU insulin equivalent /mg protein. The apparent molecular weight of the material was estimated to be 7,000. It stimulated [14C]-glucose oxidation in rat epididymal fat cells and had sulfation activity in chick chondrocytes. Furthermore, the basic ILA had a potent mitogenic activity in Balb/c-3T3 cells. Thus, the basic ILA is qualified as an 'insulin-like growth factor' (IGF). It is obviously different from somatomedin A, and may be closely related to IGF-I or somatomedin C. Subsequently, RRA for the basic ILA was developed in serum concentration of the basic ILA were determined. The serum concentrations of the basic ILA were high in acromegalics and low in patients with hypopituitarism. Thus, the basic ILA is entitled to be one of the IGFs.
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PMID:Basic peptide with insulin-like activity in human serum. 703 Jul 22

Transgenic mice were made by introducing extra copies of the mouse insulin-like growth factor-II (IGF-II) gene driven by the bovine keratin 10 promoter (BKVI). The adult plasma IGF-II levels were elevated at least three times in one line. In this line, there was a lower lipid content of both brown and white adipose depots at 2-4 months of age, and 40% less fat in the carcass at 7-9 months. The low lipid phenotype was not detected in the carcass at 2 weeks after birth. The lean characteristic was attributed to circulating IGF-II because the transgene was not expressed in fat. At 2-4 months of age, the transgenes oxidized more oral lipid, and less of this lipid was incorporated into the whole body and the epididymal fat. In contrast, the interscapular brown adipose tissue maintained lipid incorporation and lipoprotein lipase activity despite its reduced size. The altered activity of the brown adipose tissue may account for the gradual onset and persistence of the lean feature of the transgenic mice. There were no substantial changes in lipogenesis which could account for the low fat content. The plasma levels of IGF-I, insulin, glycerol, non-esterified fatty acids, triacylglycerols and glucose were not greatly changed and the pituitary GH content was within the normal range.
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PMID:High plasma insulin-like growth factor-II and low lipid content in transgenic mice: measurements of lipid metabolism. 783 87

In several studies, the anabolic hormones insulin-like growth factor-1 (IGF-1) and insulin attenuated several metabolic changes associated with cancer cachexia. In the present study, we evaluated the effect of these hormones on the cachexia associated with colon-26 (C-26) tumor. Healthy age-matched and tumor-bearing mice were treated with two daily doses of IGF-1 (50 micrograms/kg in toto), or insulin (1 U in toto). Determinants of cachexia were body and tumor weight, epididymal fat pad and serum glucose concentrations. Neither IGF-1 nor insulin treatment had a significant effect on the cachectic parameters of C-26-bearing mice. These hormones were biologically active, being capable of inducing weight gain in hypophysectomized mice and hypoglycemia, respectively. Although IGF-1 and insulin have been used to treat cancer-related weight loss, the research presented here suggests that the beneficial effect of these hormones is not universal.
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PMID:The lack of an effect by insulin or insulin-like growth factor-1 in attenuating colon-2-mediated cancer cachexia. 861 11

To determine whether leptin has insulin sensitizing effects in normal rodents, we measured plasma glucose and insulin concentrations in male Sprague-Dawley rats treated with leptin or vehicle by continuous s.c. infusion for 48 h. In additional experiments, we examined the acute effect of i.v. leptin upon insulin sensitivity under conditions of clamped glycemia. Subcutaneous leptin was administered at 10.0 and 1.0 microg/h. To avoid confounding effects of differences in food intake, both leptin- and vehicle-treated rats were fasted during the 48-h period of infusion. Infusion of leptin, 10 microg/h, significantly reduced both plasma glucose and insulin. Leptin, 1.0 microg/h, also decreased plasma glucose and insulin, although the effects on insulin did not achieve statistical significance. Leptin at either dose did not alter body weight or epididymal fat mass compared with vehicle treated controls. Leptin, 10 microg/h, decreased circulating insulin-like growth factor-1 levels. No differences in GLUT-4 content in either in brown or epididymal fat were observed as a result of leptin-treatment. Leptin, 10 microg/h, significantly decreased urine osmolality, increased water intake, and reduced renal potassium excretion compared with vehicle-infused rats. In additional rats, we measured the acute effect of i.v. leptin on insulin sensitivity determined as whole body glucose utilization during hyperinsulinemic glucose clamps performed at glucose targets of 60 and 90 mg/100 ml. Glucose utilization was increased by 29% during the last 135 min of glycemia clamped at 60 mg/100 ml (P < 0.05) and by 30% during the last 135 min of glycemia clamped at 90 mg/dl (P < 0.01) in rats infused with leptin compared with vehicle. In summary, leptin increased insulin sensitivity in normal rats both under fasting conditions and in the presence of hyperinsulinemia at clamped glucose. These effects did not appear dependent on altered body weight. Leptin also altered salt and water metabolism under fasting conditions resulting in increased water intake and more dilute urine.
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PMID:Effects of leptin on insulin sensitivity in normal rats. 923 93

Aging is accompanied by impaired angiogenesis and deficient expression of several angiogenic growth factors. To test the hypothesis that replacement of these factors would improve angiogenesis in aged animals, we cultured microvessels derived from the epididymal fat pad of aged and young mice ("aged" and "young" microvessels) in three-dimensional collagen gels for 2 weeks and measured their sprouting (formation of branch points) in response to fetal bovine serum (FBS), endothelial cell growth supplement (ECGS), and the specific growth factors transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF). In the presence of culture medium with 1% FBS (Minimal medium), sprouting of aged microvessels was significantly less than sprouting of young microvessels. The addition of high levels of FBS and ECGS to Minimal medium enhanced the sprouting of microvessels from aged mice to a greater degree than that of young mice, such that the difference between the two age groups was no longer significant. Formation of branch points by aged microvessels was also significantly increased by Minimal medium supplemented with TGF-beta1, bFGF, IGF-1, or VEGF (listed in order of highest to lowest stimulation). Sprouts generated in the presence of VEGF possessed a particularly high percentage of endothelial cells. Mitomycin C did not diminish the degree of sprouting induced by TGF-beta1, VEGF, or IGF-1, a result indicating that early stages of angiogenesis, including formation of branch points, do not require cell division. From our findings in vitro, we propose that age-related deficiencies in angiogenesis in vivo are likely to be due, in part, to a decrease in angiogenic growth factors in the extracellular milieu.
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PMID:Growth factors reverse the impaired sprouting of microvessels from aged mice. 965 26

Differentiation of precursor cells into mature fat cells is accompanied by enhanced expression of insulin-like growth factor (IGF)-I and is stimulated by multiple hormones including growth hormone, glucocorticoids, IGF-I and insulin. We used transgenic mice that overexpress insulin-like growth factor binding protein-1 to investigate the role of IGF-I in the accumulation of fat tissue. In response to a sucrose-enriched diet, transgenic mice gained significantly less body weight and the epididymal fat mass was significantly reduced compared with wild-type mice. The increase in adipocyte size was also significantly reduced in transgenic mice compared with wild-type mice. Fewer colonies were generated from adipose tissue from transgenic mice and the mitogenic response of these cells to IGF-I was significantly reduced compared with those from wild-type mice. Induction of glycerol-3-phosphate dehydrogenase, a measure of adipocyte differentiation, by IGF-I but not insulin, was reduced in preadipocytes from transgenic mice. These data indicate that IGF-I has a critical role in the proliferation of adipocyte precursors, the differentiation of preadipocytes and the development of obesity in response to calorie excess.
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PMID:Impaired adipogenesis in insulin-like growth factor binding protein-1 transgenic mice. 1046 38

Neuropeptide Y (NPY) in the hypothalamus exerts multiple physiological functions including stimulation of adipogenic pathways such as feeding and insulin secretion as well as inhibition of the somatotropic and gonadotropic axes. Since hypothalamic NPY-ergic activity is increased by negative energy balance, NPY enables coordinated regulation of growth and reproduction in parallel with energy availability. Chronic pathological increases in central NPY-ergic activity contribute to obesity. Many of the adipogenic effects of NPY are specifically dependent on adrenal glucocorticoids. However, in the current study we show that central NPY does not require adrenal hormones to inhibit the somatotropic and gonadotropic axes in rats. Male adrenalectomized and sham-operated normal rats were intracerebroventricularly (ICV) infused with NPY (15 microg/day) or saline for 5-7 days, and plasma leptin, insulin-like growth factor (IGF-1) and testosterone were assayed, and epididymal white adipose tissue (WATe) was weighed. In normal intact rats, WATe weight and leptinemia were significantly increased by NPY, and these effects were prevented by adrenalectomy. In normal rats, NPY markedly reduced plasma IGF-1 levels (470 +/- 40 versus 1260 +/- 90 ng/ml) and testosterone (0.53 +/- 0.28 versus 5.4 +/- 0.80 nmol/l in saline-infused controls, p < 0.0001). Adrenalectomy decreased plasma IGF-1 concentrations to 290 +/- 30 (p < 0.0001 versus normal rats), which were significantly reduced further by NPY. However, adrenalectomy had no significant effect on basal nor on NPY-induced plasma testosterone concentrations. In conclusion unlike the stimulatory effects of NPY on fat mass and leptinemia, NPY-induced inhibition of the somatotropic and gonadotropic axes in male rats do not require adrenal hormones.
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PMID:Inhibitory effects of central neuropeptide Y on the somatotropic and gonadotropic axes in male rats are independent of adrenal hormones. 1128 3


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