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)

Thiazolidinediones are antidiabetic agents, which not only improve glucose metabolism but also reduce blood triglyceride concentrations. These compounds are synthetic ligands for PPAR gamma, a transcription factor belonging to the nuclear receptor subfamily of PPARs, which are important transcriptional regulators of lipid and lipoprotein metabolism. The goal of this study was to evaluate the influence of a potent thiazolidinedione, BRL49653, on serum lipoproteins and to determine whether its lipid-lowering effects are mediated by changes in the expression of key genes implicated in lipoprotein metabolism. Treatment of normal rats for 7 days with BRL49653 decreased serum triglycerides in a dose-dependent fashion without affecting serum total and HDL cholesterol and apolipoprotein (apo) A-I and apo A-II concentrations. The decrease in triglyceride concentrations after BRL49653 was mainly due to a reduction of the amount of VLDL particles of unchanged lipid and apo composition. BRL49653 treatment did not change triglyceride production in vivo as analyzed by injection of Triton WR-1339, indicating a primary action on triglyceride catabolism. Analysis of the influence of BRL49653 on the expression of LPL and apo C-III, two key players in triglyceride catabolism, showed a dose-dependent increase in mRNA levels and activity of LPL in epididymal adipose tissue, whereas liver apo C-III mRNA levels remained constant. Furthermore, addition of BRL49653 to primary cultures of differentiated adipocytes increased LPL mRNA levels, indicating a direct action of the drug on the adipocyte. Simultaneous administration of BRL49653 and fenofibrate, a hypolipidemic drug that acts primarily on liver through activation of PPAR alpha both decreased liver apo C-III and increased adipose tissue LPL mRNA levels, resulting in a more pronounced lowering of serum triglycerides than each drug alone. In conclusion, both fibrates and thiazolidinediones exert a hypotriglyceridemic effect. While fibrates act primarily on the liver by decreasing apo C-III production, BRL49653 acts primarily on adipose tissue by increasing lipolysis through the induction of LPL expression. Drugs combining both PPAR alpha and gamma activation potential should therefore display a more efficient hypotriglyceridemic activity than either compound alone and may provide a rationale for improved therapy for elevated triglycerides.
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PMID:Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complementary mechanism relative to fibrates. 932 74

Leptin, the ob gene product, is an adipocyte-secreted hormone that centrally regulates weight by decreasing caloric intake and increasing energy expenditure. Expression of leptin is regulated by dietary status, insulin, glucocorticoids and catecholamines. Pancreastatin (PST), a chromogranin A-derived peptide, correlates with catecholamine levels, and may play a role in the physiology of stress, modulating endocrine secretion and metabolism. Thus, PST has been found to exert a lipolytic and anti-insulin effect in white adipocytes. The aim of the present work was to investigate a possible role of PST modulating the expression of key genes involved in lipid storage and metabolism: leptin, PPAR-gamma2, UCP-1 and UCP-2. We incubated isolated rat epididymal adipocytes with 100 nM PST for 16 and 24 h. Leptin, UCP-2 and UCP-1 mRNA levels were assessed by RT-PCR, followed by Southern blot. Leptin secretion was also measured by ELISA. PST inhibited leptin expression and secretion at 16-h incubation, but this effect was no longer observed after 24 h. On the other hand, PST stimulated the expression of UCP-2 after 16 h. However, the effect was still significant after 24 h. The inhibitory effect of PST on leptin expression and secretion and the stimulation of UCP-2 expression were prevented by blocking PKC. UCP-1 and PPR-gamma2 expression did not change after PST stimulation. Leptin differentially regulates the expression of key genes in the rat adipocyte, upregulating the expression of UCP-2 and inhibiting the expression and secretion of leptin by a mechanism that involves PKC activity. These effects may contribute to the metabolic action of catecholamines in physiological and pathophysiological conditions with increased sympathetic activity.
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PMID:Pancreastatin, a chromogranin A-derived peptide, inhibits leptin and enhances UCP-2 expression in isolated rat adipocytes. 1468 97

Insulin-induced gene 1 (INSIG-1) is a key regulator in the processing of the sterol regulatory element-binding proteins (SREBPs). We demonstrated that Insig-1 is regulated by peroxisome proliferator-activated receptor gamma (PPARgamma) providing a link between insulin sensitization/glucose homeostasis and lipid homeostasis. Insig-1 was identified as a PPARgamma target gene using microarray analysis of mRNA from the white adipose tissue of diabetic (db/db) animals treated with PPARgamma agonists. Insig-1 was induced in subcutaneous (9-fold) and epididymal (4-fold) fat pads from db/db mice treated for 8 days with the PPARgamma agonist rosiglitazone (30 mg/kg/day). This in vivo response was confirmed in differentiated C3H10T1/2 adipocytes treated with rosiglitazone. To elucidate the molecular mechanisms regulating INSIG-1 expression, we cloned and characterized the human INSIG-1 promoter. Co-expression of PPARgamma and RXRalpha transactivated the INSIG-1 promoter in the presence of PPARgamma agonists. This induction was attenuated when a dominant negative PPARgamma construct was transfected into cells. Furthermore, a PPARgamma antagonist repressed the transactivation of the INSIG-1 promoter-reporter construct. Truncations of the promoter resulted in the identification of a PPAR response element that mediated the regulation of the promoter. We demonstrated with recombinant proteins that the PPARgamma/RXRalpha heterodimer binds directly to this PPAR response element. In addition to regulation by PPARgamma/RXRalpha, we demonstrated that the INSIG-1 promoter is regulated by transcriptionally active SREBP. The sterol response element was identified 380 base pairs upstream of the transcriptional start site. These findings suggest that the regulation of Insig-1 by PPARgamma agonists could in turn regulate SREBP processing and thus couple insulin sensitizers with the regulation of lipid homeostasis.
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PMID:Rosiglitazone induction of Insig-1 in white adipose tissue reveals a novel interplay of peroxisome proliferator-activated receptor gamma and sterol regulatory element-binding protein in the regulation of adipogenesis. 1507 65

Dehydroepiandrosterone (DHEA), the most abundant steroid hormone in human blood, is considered to be one of fat-reducing hormones. However, the molecular mechanisms underlying DHEA mode of action in obesity has not been fully clarified. The pivotal role in the maintenance of cellular lipid and energy balance is played by peroxisome proliferator-activated receptor alpha (PPARalpha) which acts as transcriptional activator of numerous genes encoding enzymes involved in fatty acid catabolism. Lately published papers suggest that resistin, a low molecular-weight protein produced by adipose tissue, may act as an inhibitor of adipocyte differentiation and could regulate adipose tissue mass. Recent studies have established that the promoter region of the resistin gene contains several putative PPAR response elements. Since DHEA has been characterized as a peroxisome proliferator able to induce hepatic genes through PPARalpha, we hypothesised that DHEA might affect PPARalpha and, subsequently, resistin gene expression in adipose tissue. In order to test this hypothesis, an experiment was performed comparing PPARalpha and resistin gene expression in white adipose tissue (WAT) of male Wistar rats fed standard or DHEA-supplemented (0.6% (w/w)) diet for 2 weeks. DHEA administration to the rats induced PPARalpha and resistin gene expression in WAT (3- and 2.25-fold, respectively; as determined by real-time reverse transcription-polymerase chain reaction (RT-PCR)); reduced body weight, epididymal adipose tissue mass and decreased serum leptin levels. We propose that DHEA may impact on the transcription of resistin gene through a mechanism involving PPARalpha and that an elevated resistin level may lead to an inhibition of adipogenesis and a decrease in adipose tissue mass.
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PMID:Dehydroepiandrosterone up-regulates resistin gene expression in white adipose tissue. 1513 May 11

Dehydroepiandrosterone (DHEA), an adrenal steroid, is known to decrease body fat. Thus, it may also alter the endocrine functions of adipose tissue. The aim of this study was to determine if administration of DHEA might influence adiponectin gene expression and secretion from adipose tissue. We demonstrate here the inducing effect of exogenously administered DHEA on adiponectin gene expression in epididymal WAT and adiponectin levels in serum of rats fed a DHEA-containing diet (0.6%, w/w) for 2 weeks, accompanied by a reduction in epididymal adipose tissue mass. A corresponding increase in peroxisome proliferator-activated receptor gamma (PPAR(gamma)) mRNA expression suggests that PPAR(gamma) may be involved in the up-regulation of adiponectin gene expression after DHEA treatment. The presented observations indicate that the positive effects of DHEA, which seems to play a protective role against insulin resistance and atherosclerosis, may be in fact indirect and due to up-regulation of adiponectin gene expression and stimulation of adiponectin secretion from adipose tissue.
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PMID:Effect of DHEA on endocrine functions of adipose tissue, the involvement of PPAR gamma. 1590 96

Exercise training and regular physical activity increase oxidation of fat. Enhanced oxidation of fat is important for preventing lifestyle diseases such as hypertension and obesity. The aim of the present study in rats was to determine whether intake of dietary soya protein and exercise training have an additive effect on the activity and mRNA expression of enzymes involved in skeletal muscle fatty acid oxidation. Male Sprague-Dawley rats (n 32) were assigned randomly into four groups (eight rats per group) and then divided further into sedentary or exercise-trained groups fed either casein or soya protein diets. Rats in the exercise groups were trained for 2 weeks by swimming for 120 min/d, 6 d/week. Exercise training decreased hepatic triacylglycerol levels and retroperitoneal adipose tissue weight and increased skeletal muscle carnitine palmitoyltransferase 1 (CPT1) activity and mRNA expression of CPT1, beta-hydroxyacyl-CoA dehydrogenase (HAD), acyl-CoA oxidase, PPARgamma coactivator 1alpha (PGC1alpha) and PPARalpha. Soya protein significantly decreased hepatic triacylglycerol levels and epididymal adipose tissue weight and increased skeletal muscle CPT1 activity and CPT1, HAD, acyl-CoA oxidase, medium-chain acyl-CoA dehydrogenase, PGC1alpha and PPARalpha mRNA levels. Furthermore, skeletal muscle HAD activity was the highest in exercise-trained rats fed soya protein. We conclude that exercise training and soya protein intake have an important additive role on induction of PPAR pathways, leading to increased activity and mRNA expression of enzymes involved in fatty acid oxidation in skeletal muscle and reduced accumulation of body fat.
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PMID:Dietary soya protein intake and exercise training have an additive effect on skeletal muscle fatty acid oxidation enzyme activities and mRNA levels in rats. 1692 51

The aim of the present study was to examine the effect of 8 weeks of voluntary wheel running on the gene expression, at the protein level, of 2 enzymes involved in lipogenesis (fatty acid synthase [FAS] and diacylglycerol acyl transferase 1), 2 proteins involved in lipolysis (hormone-sensitive lipase [HSL] and perilipin), and 3 transcription factors mediating the induction of genes involved in lipid metabolism (the alpha, gamma, and delta members of the peroxisome proliferator-activated receptor, or PPAR, family) in rat liver, gastrocnemius muscle, epididymal fat, and subcutaneous fat. Proteins were measured through Western blot analysis in the tissues of 11 trained and 14 untrained rats. The trained rats had lower FAS in the liver; higher FAS, HSL, and perilipin in epididymal fat; and higher HSL in subcutaneous fat. In addition, the trained rats had higher total protein concentrations in both fat depots. No significant differences in the liver, muscle, or adipose tissue PPAR contents were found between groups. However, the DNA binding activity of PPARgamma, measured through an enzyme immunoassay-based method, was higher in both fat depots of the trained rats. Our findings suggest that long-term wheel running had significant effects on the concentrations of proteins playing key roles in lipogenesis and lipolysis in rat liver and adipose tissue. These effects may be due to PPAR activation rather than induction, rendering the transcriptional regulation of target genes more economical and flexible. The activation of PPARgamma with exercise may mediate its beneficial effect on insulin sensitivity.
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PMID:Long-term exercise increases the DNA binding activity of peroxisome proliferator-activated receptor gamma in rat adipose tissue. 1761 46

The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPARgamma target genes that may contribute to the reduction of circulating free fatty acids after TZD treatment have been identified, the relevant PPARgamma target genes that may exert the anti-lipolytic effect of TZDs are unknown. Here we identified the anti-lipolytic human G-protein-coupled receptor 81 (GPR81), GPR109A, and the (human-specific) GPR109B genes as well as the mouse Gpr81 and Gpr109A genes as novel TZD-induced genes in mature adipocytes. GPR81/Gpr81 is a direct PPARgamma target gene, because mRNA expression of GPR81/Gpr81 (and GPR109A/Gpr109A) increased in mature human and murine adipocytes as well as in vivo in epididymal fat pads of mice upon rosiglitazone stimulation, whereas small interfering RNA-mediated knockdown of PPARgamma in differentiated 3T3-L1 adipocytes showed a significant decrease in Gpr81 protein expression. In addition, chromatin immunoprecipitation sequencing analysis in differentiated 3T3-L1 cells revealed a conserved PPAR:retinoid X receptor-binding site in the proximal promoter of the Gpr81 gene, which was proven to be functional by electromobility shift assay and reporter assays. Importantly, small interfering RNA-mediated knockdown of Gpr81 partly reversed the inhibitory effect of TZDs on lipolysis in 3T3-L1 adipocytes. The coordinated PPARgamma-mediated regulation of the GPR81/Gpr81 and GPR109A/Gpr109A genes (and GPR109B in humans) presents a novel mechanism by which TZDs may reduce circulating free fatty acid levels and perhaps ameliorate insulin resistance in obese patients.
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PMID:Peroxisome proliferator-activated receptor gamma regulates expression of the anti-lipolytic G-protein-coupled receptor 81 (GPR81/Gpr81). 1963 98

Adipocyte differentiation is an important aspect in energy homeostasis. Although the regulation of adipocyte differentiation is relatively well understood, the underlying molecular mechanism remains unclear. In this study, subcutaneous and epididymal adipose tissues were used to study the differential expression of associated genes. We found that the expression level of mouse homologue of rat prostatic androgen-repressed message-1 (mPARM-1) gene was higher in subcutaneous, perirenal and mesenteric adipose tissues than in epididymal adipose tissue. In mouse subcutaneous, perirenal, and mesenteric adipose tissues, the expression level of this gene was higher in adipocytes than in non-adipocyte cells, i.e. stromal-vascular cells. Furthermore, mPARM-1 mRNA expression was up-regulated in subcutaneous, mesenteric, and epididymal adipose tissues of mice fed a high-fat diet compared to those fed a normal-fat diet. Expression level of mPARM-1 mRNA increased in the early stage of the chemically induced adipocyte differentiation, preceding the increase in peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma2) mRNA. Tumor necrosis factor-alpha (TNF-alpha), an inhibitor of adipocyte differentiation, reduced the expression of mPARM-1 mRNA in differentiated 3T3-L1 cells and subsequently down-regulated the expression of adipogenic genes, including PPAR-gamma2, leptin and adipogenin. Moreover, knockdown of mPARM-1 expression with siRNA reduced lipid accumulation and the expression levels of PPAR-gamma2 and adipocyte protein 2 mRNAs, which suggest that the degree of adipocyte differentiation of 3T3-L1 cells has been reduced. These results indicate that mPARM-1 might be involved in the regulation of fat accumulation and adipocyte differentiation.
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PMID:Prostatic androgen-repressed message-1 as a regulator of adipocyte differentiation in the mouse. 1996 31

The kinetics of metabolic and inflammatory parameters associated with obesity were evaluated in a murine diet-induced obesity (DIO) model using a diet high in fat and cholesterol. Cellular infiltration and mediator production were assessed and shown to be therapeutically modulated by the PPARgamma agonist rosiglitazone. C57BL/6 mice were maintained on a 45% fat/ 0.12% cholesterol (HF/CH) or Chow diet for 3, 6, 16, or 27 weeks. Flow cytometry was employed to monitor peripheral blood monocytes and adipose tissue macrophages (ATM). Gene expression and protein analysis methods were used to evaluate mediator production from total epididymal fat (EF), stromal vascular fraction (SVF), and sorted SVF cells. To investigate therapeutic intervention, mice were fed a HF/CH diet for 12 weeks and then a diet formulated with rosiglitazone (5 mg/kg) for an additional 6 weeks. A HF/CH diet correlated with obesity and a dramatic proinflammatory state. Therapeutic intervention with rosiglitazone attenuated the HF/CH induced inflammation. In addition, a novel population was found that expressed the highest levels of the pro-inflammatory mediators CCL2 and IL-6.
PPAR Res 2010
PMID:Kinetic assessment and therapeutic modulation of metabolic and inflammatory profiles in mice on a high-fat and cholesterol diet. 2044 33


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