Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.79 (hormone-sensitive lipase)
 2,163 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Human omental adipocytes display a range of biochemical properties that distinguish them from adipocytes of subcutaneous origin. However, information about site-related gene expression in human fat cells is limited. We have previously demonstrated that leptin mRNA is markedly overexpressed in abdominal subcutaneous (SC) compared with omental (Om) adipocytes. To further investigate depot-specific differences in adipocyte gene expression, we have measured, in paired samples of isolated human adipocytes obtained from SC and Om fat depots, the expression of mRNAs encoding a number of proteins involved in the control of adipocyte metabolism. In contrast to the marked site-related expression of leptin, genes encoding lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and adipsin were not consistently differentially expressed. Of note, a highly significant inverse correlation between adipocyte PPAR-gamma expression and BMI (r = -0.7, P = 0.0005) was found. In parallel experiments, differential display was used in an attempt to identify novel and/or unexpected adipocyte genes that were expressed in a site-related manner. No transcript that was unique to one or another depot was found, but cellular inhibitor of apoptosis protein-2 (cIAP2) mRNA, which has not previously been reported in adipocytes, was expressed at higher levels in Om than SC adipocytes (Om > SC in all eight subjects; mean Om:SC ratio 1.9 +/- 0.2, P < 0.01). Because cIAP2 may be involved in the regulation of TNF-alpha signaling, this raises the possibility that depot-specific differences may exist in the regulation of adipocyte apoptosis. Thus, of the mRNAs examined to date, only leptin and cIAP2 show consistent site-related expression, suggesting that these molecules may have important roles in determining functional properties particular to individual adipose depots. Given the importance of PPAR-gamma in adipocyte development and insulin sensitivity, the inverse correlation between adipocyte PPAR-gamma mRNA levels and adiposity may represent a local regulatory mechanism restraining fat accumulation and/or may be related to the reduction of insulin sensitivity that occurs with increasing fat mass.
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PMID:Depot-related gene expression in human subcutaneous and omental adipocytes. 972 25

As part of an ongoing search for susceptibility genes in obese families, we performed linkage analyses in 101 French families between qualitative and quantitative traits related to morbid obesity and polymorphisms located in or near 15 candidate genes whose products are involved in body weight regulation. These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3-adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone-sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransferase-1 (CPT-1). Phenotypes related to obesity such as BMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acids were used for nonparametric sib-pair analyses. A weak indication for linkage was obtained between the Isl-1 locus and obesity status defined by a z score over one SD of BMI (n = 226 sib pairs, pi = 0.54 +/- 0.02, P = 0.03). Moreover, a suggestive indication for linkage was found between the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and leptin adjusted for BMI (P = 0.0001). Multipoint analyses for leptin trait with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. Although marginally positive indications for linkage in subgroups of families were found with IRS-1, CPT-1, and HSL loci, our data suggested that these genes are not major contributors to obesity. Whether an obesity susceptibility gene (Isl-1 itself or another nearby gene) lies on chromosome 5q should be determined by further analyses.
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PMID:A sib-pair analysis study of 15 candidate genes in French families with morbid obesity: indication for linkage with islet 1 locus on chromosome 5q. 1033 20

Lipolysis is an important process determining fuel metabolism, and insulin regulates this process in adipose tissue. The aim of this study was to investigate the long-term effects of insulin, an insulin enhancer (rosiglitazone [RSG]), and insulin in combination with RSG on the regulation of lipolysis and lipogenesis in human abdominal subcutaneous fat. Lipolysis and lipogenesis were assessed by protein expression studies of hormone-sensitive lipase (HSL) (84 kDa) and lipoprotein lipase (LPL) (56 kDa), respectively. In addition, lipolytic rate was assessed by glycerol release assay and tumor necrosis factor (TNF)-alpha release measured by enzyme-linked immunosorbent assay (n = 12). In subcutaneous adipocytes, increasing insulin doses stimulated LPL expression, with maximal stimulation at 100 nmol/l insulin (control, 1.0 +/- 0.0 [mean +/- SE, protein expression relative to control]; 1 nmol/l insulin, 0.87 +/- 0.13; 100 nmol/l insulin, 1.68 +/- 0.19; P < 0.001). In contrast, insulin at the 100 nmol/l dose reduced the expression of HSL (100 nmol/l insulin, 0.49 +/- 0.05; P < 0.05), while no significant reduction was observed at other doses. Higher doses of insulin stimulated both HSL (1,000 nmol/l insulin, 1.4 +/- 0.07; P < 0.01) and LPL (control 1.00 +/- 0.0; 1,000 nmol/l insulin, 2.66 +/- 0.27; P < 0.01) protein expression. Cotreatment with RSG induced an increased dose response to insulin for LPL and HSL (P < 0.05); RSG alone also increased LPL and HSL expression (P < 0.05). Insulin stimulated TNF-alpha secretion in a dose-dependent manner (P < 0.01); the addition of RSG (10(-8) mol/l) reduced TNF-alpha secretion (P < 0.05). In summary, chronic treatment of human adipocytes with insulin stimulates lipolysis and LPL protein expression. The addition of RSG reduced the lipolytic rate and TNF-alpha secretion. The increase in lipolysis is not explained by changes in HSL expression. These data, therefore, may explain in part why hyperinsulinemia coexists with increased circulating nonesterified free fatty acids and increased adiposity in obese and/or type 2 diabetic patients.
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PMID:Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro. 1197 47

Primary culture of adipose tissue has often been used to investigate pharmacological and nutritional regulation of adipocyte gene expression. Possible alteration of adipocyte gene expression by primary culture on its own has not been explored in detail. In order to address this issue, explants were prepared from human subcutaneous adipose tissue recovered from plastic surgery and maintained for 0 to 48 h in DMEM supplemented with 10 % serum. At different time points, adipocytes were isolated from the explants by collagenase digestion, and mRNA expression and lipolysis were studied. Culture was associated with an accumulation of tumor necrosis factor-alpha (TNFalpha) in the culture medium, an increase in anaerobic glycolysis, and an increase in the basal lipolysis. In parallel, a rapid and dramatic decrease in the level of mRNA encoding for several adipocyte-specific proteins such as adipocyte lipid-binding protein, hormone-sensitive lipase, lipoprotein lipase, and peroxisome proliferation activating receptor-gamma2 was observed in isolated adipocytes. These downregulations were reminiscent of a dedifferentiation process. In parallel, primary culture was associated with an increase in adipocyte beta-actin, TNFalpha, glucose transporter-1 and hypoxia-induced factor-1alpha mRNAs. Treatment of explants with agents that increase cAMP (isobutylmethylxanthine and forskolin) prevented TNFalpha production and expression and culture-induced alterations of adipocyte gene expression. These data show that primary culture of human adipose tissue explants dramatically alters adipocyte gene expression.
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PMID:Culture of human adipose tissue explants leads to profound alteration of adipocyte gene expression. 1273 76

To elucidate the role of hormone-sensitive lipase (HSL) in diet-induced obesity, HSL-deficient (HSL-/-) and wild-type mice were fed normal chow or high-fat diets. HSL-/- mice were resistant to diet-induced obesity showing higher core body temperatures. Weight and triacylglycerol contents were decreased in white adipose tissue (WAT) but increased in both brown adipose tissue (BAT) and liver of HSL-/- mice. Serum insulin levels in the fed state and tumor necrosis factor-alpha mRNA levels in adipose tissues were higher, whereas serum levels of adipocyte complement-related protein of 30 kDa (ACRP30)/adiponectin and leptin, as well as mRNA levels of ACRP30/adiponectin, leptin, resistin, and adipsin in WAT, were lower in HSL-/- mice than in controls. Expression of transcription factors associated with adipogenesis (peroxisome proliferator-activated receptor-gamma, CAAT/enhancer-binding protein-alpha) and lipogenesis (carbohydrate response element-binding protein, adipocyte determination- and differentiation-dependent factor-1/sterol regulatory element-binding protein-1c), as well as of adipose differentiation markers (adipocyte lipid-binding protein, perilipin, lipoprotein lipase), lipogenic enzymes (glycerol-3-phosphate acyltransferase, acyl-CoA:diacylglycerol acyltransferase-1 and -2, fatty acid synthase, ATP citrate lyase) and insulin signaling proteins (insulin receptor, insulin receptor substrate-1, GLUT4), was suppressed in WAT but not in BAT of HSL-/- mice. In contrast, expression of genes associated with cholesterol metabolism (sterol-regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA:cholesterol acyltransferase-1) and thermogenesis (uncoupling protein-2) was upregulated in both WAT and BAT of HSL-/- mice. Our results suggest that impaired lipolysis in HSL deficiency affects lipid metabolism through alterations of adipose differentiation and adipose-derived hormone levels.
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PMID:Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice. 1295 98

The function of adipocytes derived from human mesenchymal stem cells (hMSC) was investigated for the first time in hMSC from fetal liver (FL) and adult bone marrow (BM) and compared with preadipocytes from human subcutaneous adipose tissue differentiated according to adipocyte-specific protocols. FL- and BM-derived adipocytes displayed both morphological and functional characteristics of mature adipocytes including specific intracellular signaling pathways for tumor necrosis factor-alpha, catecholamine-regulated lipolysis as well as secretion of adiponectin and leptin. Similar to differentiated preadipocytes, hMSC adipocytes displayed lipolytic effects mediated by beta-adrenoceptors and antilipolytic effects mediated by the alpha 2A-adrenoceptor (alpha 2A-AR) and expressed proteins with a pivotal role in human lipolysis, including beta 2-AR, alpha 2A-AR, and hormone-sensitive lipase. We conclude that hMSC-derived adipocytes are morphologically and functionally similar to preadipocytes and display an intact lipolytic signaling pathway and endocrine function. These systems could be of great value in adipocyte research as a renewable source of adipocytes.
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PMID:Functional characterization of human mesenchymal stem cell-derived adipocytes. 1459 27

To elucidate the mechanism for hyperlipidemia in the hepatoma-bearing state, changes in some parameters related to the lipid metabolism and serum tumor necrosis factor-alpha (TNF-alpha) level were examined in Donryu rats that had been subcutaneously implanted with an ascites hepatoma cell line of AH109A. These parameters were also examined in rats that had been given a single injection of lipopolysaccharide (LPS), a model for acute infection with TNF-alpha secretion into the blood circulation. The serum triglyceride and total cholesterol (Ch) levels were significantly higher in both the hepatoma-implanted and LPS-injected rats than in normal rats. The level of adipose tissue lipoprotein lipase was decreased by hepatoma implantation and LPS injection, while the hormone-sensitive lipase activity was increased by the same treatments. Fatty acid (FA) oxidation and Ch synthesis were also stimulated by both treatments. The serum TNF-alpha level was noticably elevated by hepatoma implantation and greatly by the LPS injection. This LPS injection increased hepatic FA synthesis. The serum high-density lipoprotein Ch level and hepatic Ch 7alpha-hydroxylase activity were not changed by the LPS injection. Hepatoma implantation led to hyperlipidemia and elevated the serum TNF-alpha level, as did the LPS injection.
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PMID:Comparison of the changes in lipid metabolism between hepatoma-bearing and lipopolysaccharide-treated rats. 1474 66

There are more than 430 chromosomic regions with gene variants involved in body weight regulation and obesity development. Polymorphisms in genes related to energy expenditure--uncoupling proteins (UCPs), related to adipogenesis and insulin resistance--hormone-sensitive lipase (HLS), peroxisome proliferator-activated receptor gamma (PPAR gamma), beta adrenergic receptors (ADRB2,3), and alfa tumor necrosis factor (TNF-alpha), and related to food intake--ghrelin (GHRL)--appear to be associated with obesity phenotypes. Obesity risk depends on two factors: a) genetic variants in candidate genes, and b) biographical exposure to environmental risk factors. It is necessary to perform new studies, with appropriate control groups and designs, in order to reach relevant conclusions with regard to gene/environmental (diet, lifestyle) interactions.
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PMID:[Obesity studies in candidate genes]. 1511 49


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