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)

Cardiovascular complications of obesity are more common in men than women. Sex differences in visceral fat lipolysis may be of importance in this respect, since increased release of free fatty acids (FFAs) from visceral fat to the liver by the portal venous system has been thought to cause several metabolic complications due to obesity, such as hypertension, hyperlipidemia, and glucose intolerance. The aim of this study was to investigate sex differences in clinical characteristics and visceral fat mobilization in obesity. Obese subjects (22 male and 23 female) undergoing elective surgery were matched for body mass index and age. The males had both higher waist-to-hip ratio (WHR), sagittal diameter, blood pressure, fat-cell volume, plasma insulin, glucose, and triglyceride and lower HDL cholesterol levels than the females. The rate of norepinephrine-induced FFA and glycerol release was twofold higher in men (P = .02). No significant reutilization of FFA was observed. The difference in maximum norepinephrine-induced rate of lipolysis between men and women was independent of both WHR and sagittal diameter and was an independent regressor for levels of plasma glucose and plasma HDL cholesterol. Fat-cell volume was an independent regressor for plasma triglycerides and blood pressure. No sex differences in the lipolytic sensitivity to beta 1- or beta 2-adrenoceptor-specific agonists or in the antilipolytic effect of insulin were observed. However, the lipolytic beta 3-adrenoceptor sensitivity was 12 times higher (P = .004) and the antilipolytic alpha 2-adrenoceptor sensitivity 17 times lower (P = .003) in men. Furthermore, lipolysis induced by agents acting at the adenylate cyclase and protein kinase A levels were almost twofold enhanced in men. However, no sex difference in maximum hormone-sensitive lipase activity was observed. In conclusion, in obesity, catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women. This phenomenon is partly due to a larger fat-cell volume but also to a decrease in the function of alpha 2-adrenoceptors, an increase in the function of beta 3-adrenoceptors, and an increased ability of cyclic AMP to activate hormone-sensitive lipase. These factors may contribute to gender-specific differences in metabolic and cardiovascular disturbances accompanied by obesity.
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PMID:Sex differences in visceral fat lipolysis and metabolic complications of obesity. 926 Dec 82

Lipoatropic diabetes (LD) is a rare recessive autosomal disorder, mainly characterized by lipoatrophy with alterations in lipid metabolism and extreme insulin resistance. To identify molecular defects responsible for this disease, we tested the implication of 14 candidate genes coding for proteins involved either in insulin action, i.e. insulin receptor, insulin receptor substrate 1, insulin-like growth factor I receptor, diabetes-associated ras-like protein (Rad), and glycogen synthase, or in lipid metabolism, i.e. lipoprotein lipase; apolipoproteins CII, AII, and CIII; hepatic lipase; hormone-sensitive lipase; the beta 3-adrenergic receptor; leptin; and fatty acid-binding protein 2. To this end, haplotype and linkage analyses using genotyping with microsatellites in 10 consanguineous families provided us with powerful genetic tools. Our results show that in most families, lod scores at a null recombination fraction were less than -2. Haplotype analysis also argues against the involvement of these genes in LD. This implies that mutations in these genes are unlikely to make a major genetic contribution to LD.
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PMID:Genetic exclusion of 14 candidate genes in lipoatropic diabetes using linkage analysis in 10 consanguineous families. 932 83

The metabolism of free fatty acids (FFA) is altered in two common atherosclerosis-promoting disorders: familial combined hyperlipidemia (FCHL) and insulin resistance syndrome (IRS). It has been suggested that these two conditions may have a common etiology. The enzymes lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) are rate-limiting steps for the turnover of fatty acids in adipose tissue, because they hydrolyze extracellular triglycerides in lipoproteins (LPL) and intracellular triglycerides in adipocytes (HSL). The present study was undertaken to simultaneously determine the activities of LPL and HSL in subcutaneous adipose tissue from male patients with FCHL and IRS. LPL and HSL activity was investigated in 10 nonobese FCHL patients and compared with 10 matched healthy nonobese subjects, and in 8 essentially normolipidemic IRS patients (who did not have overt diabetes mellitus) and compared with 9 nonobese matched control subjects. LPL activity was 43% lower in patients with IRS (P < .0005), as compared with control subjects, but HSL activity was not significantly different in the two groups, On the other hand, HSL activity was decreased by 45% in FCHL patients (P < .01), as compared with control subjects, but LPL activity was not significantly different in FCHL patients and the control group. In conclusion, triglyceride metabolism in adipose tissue is altered in both FCHL and IRS. However, the abnormalities observed involve impaired function of LPL in IRS and impaired function of HSL in FCHL, suggesting separate etiologies for the altered lipolysis in these conditions, at least in male subjects.
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PMID:Adipose tissue lipoprotein lipase and hormone-sensitive lipase. Contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome. 935 2

Cortisol is known to increase whole body lipolysis, yet chronic hypercortisolemia results in increased fat mass. The main aim of the study was to explain these two apparently opposed observations by examining the acute effects of hypercortisolemia on lipolysis in subcutaneous adipose tissue and in the whole body. Six healthy subjects were studied on two occasions. On one occasion hydrocortisone sodium succinate was infused i.v. to induce hypercortisolemia (mean plasma cortisol concentrations, 1500 +/- 100 vs. 335 +/- 25 nmol/L; P < 0.001); on the other occasion (control study) no intervention was made. Lipolysis in the s.c. adipose tissue of the anterior abdominal wall was studied by measurement of arterio-venous differences, and lipolysis in the whole body was studied by constant infusion of [1,2,3-2H5]glycerol for measurement of the systemic glycerol appearance rate. Hypercortisolemia led to significantly increased arterialized plasma nonesterified fatty acid (NEFA; P < 0.01) and blood glycerol concentrations (P < 0.05), with an increase in systemic glycerol appearance (P < 0.05). However, in s.c. abdominal adipose tissue, hypercortisolemia decreased veno-arterialized differences for NEFA (P < 0.05) and reduced NEFA efflux (P < 0.05). This reduction was attributable to decreased intracellular lipolysis (P < 0.05), reflecting decreased hormone-sensitive lipase action in this adipose depot. Hypercortisolemia caused a reduction in arterialized plasma TAG concentrations (P < 0.05), but without a significant change in the local extraction of TAG (presumed to reflect the action of adipose tissue lipoprotein lipase). There was no significant difference in plasma insulin concentrations between the control and hypercortisolemia study. Site-specific regulation of the enzymes of intracellular lipolysis (hormone-sensitive lipase) and intravascular lipolysis (lipoprotein lipase) may explain the ability of acute cortisol treatment to increase systemic glycerol and NEFA appearance rates while chronically promoting net central fat deposition.
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PMID:Effects of physiological hypercortisolemia on the regulation of lipolysis in subcutaneous adipose tissue. 946 84

Phosphodiesterases (PDEs) include a large group of structurally related enzymes that belong to at least seven related gene families (PDEs 1-7) that differ in their primary structure, affinity for cAMP and cGMP, response to specific effectors, sensitivity to specific inhibitors, and regulatory mechanism. One characteristic of PDE3s involves their phosphorylation and activation in response to insulin as well as to agents that increase cAMP in adipocytes, hepatocytes, and platelets and in response to insulin-like growth factor 1 in pancreatic beta cells. In adipocytes, activation of the membrane-associated PDE3B is the major mechanism whereby insulin antagonizes catecholamine-induced lipolysis. PDE3B activation results in increased degradation of cAMP and, thereby, a lowering of the activity of cAMP-dependent protein kinase (PKA). The reduced activity of PKA leads to a net dephosphorylation and decreased activity of hormone-sensitive lipase and reduced hydrolysis of triglycerides. Activation of the rat adipocyte PDE3B by insulin is associated with phosphorylation of serine-302. The mechanism whereby insulin stimulation leads to phosphorylation/activation of PDE3B is only partly understood. In rat adipocytes, lipolytic hormones and other agents that increase cAMP, including isoproterenol, also induce rapid phosphorylation, presumably catalyzed by PKA, of serine-302 of PDE3B. The phosphorylation is associated with activation of the enzyme, most likely representing "feedback" regulation of cAMP, presumably allowing close coupling of the regulation of steady-state concentrations of both cAMP and PKA and, thereby, control of lipolysis. In the review we describe methods and strategies used in the authors' laboratories to study phosphorylation and activation of PDE3B in adipocytes and in vitro.
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PMID:Phosphorylation and activation of hormone-sensitive adipocyte phosphodiesterase type 3B. 950 Aug 57

Thiazolidinediones (TZDs) such as BRL 49653 are a class of antidiabetic agents that are agonists for the peroxisome proliferator-activated nuclear receptor (PPAR-gamma2). In vivo, TZDs reduce circulating levels of free fatty acids (FFAs) and ameliorate insulin resistance in individuals with obesity and NIDDM. Adipocyte production of TNF-alpha is proposed to play a role in the development of insulin resistance, and because BRL 49653 has been shown to antagonize some of the effects of TNF-alpha, we examined the effects of TNF-alpha and BRL 49653 on adipocyte lipolysis. After a 24-h incubation of TNF-alpha (10 ng/ml) with 3T3-L1 adipocytes, glycerol release increased by approximately 7-fold, and FFA release increased by approximately 44-fold. BRL 49653 (10 pmol/l) reduced TNF-alpha-induced glycerol release by approximately 50% (P < 0.001) and FFA release by approximately 90% (P < 0.001). BRL 49653 also reduced glycerol release by approximately 50% in adipocytes pretreated for 24 h with TNF-alpha. Prolonged treatment (5 days) with either BRL 49653 or another PPAR-gamma2 agonist, 15-d delta-12,14-prostaglandin J2 (15-d deltaPGJ2), blocked TNF-alpha-induced glycerol release by approximately 100%. Catecholamine (isoproterenol)-stimulated lipolysis was unaffected by BRL 49653 and 15-d deltaPGJ2. BRL 49653 partially blocked the TNF-alpha-mediated reduction in protein levels of hormone-sensitive lipase and perilipin A, two proteins involved in adipocyte lipolysis. These data suggest a novel pathway that may contribute to the ability of the TZDs to reduce serum FFA and increase insulin sensitivity.
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PMID:BRL 49653 blocks the lipolytic actions of tumor necrosis factor-alpha: a potential new insulin-sensitizing mechanism for thiazolidinediones. 956 6

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

Mechanisms regulating adipocyte lipolysis are reviewed in three stages. The first stage examines plasma membrane hormone receptors and G-proteins. The primary regulators of adipose tissue lipolysis, the catecholamines, bind to the alpha 2, beta 1, beta 2, and beta 3 adrenergic receptors. The alpha 2 receptor couples with Gi-proteins to inhibit cyclic AMP formation and lipolysis, while the beta receptors couple with Gs-proteins to stimulate cyclic AMP formation and lipolysis. The beta 1 receptor may mediate low level catecholamine stimulation, while the beta 3 receptor, which is activated by higher levels of catecholamines, may deliver a more sustained signal. The second stage examines the regulation of cyclic AMP, the intracellular messenger that activates protein kinase A. Adenylyl cyclase synthesizes cyclic AMP from ATP and is regulated by the G-proteins. Phosphodiesterase 3B hydrolyzes cyclic AMP to AMP and is activated and phosphorylated by both insulin and the catecholamines norepinephrine and epinephrine. The third stage focuses on the rate-limiting enzyme of lipolysis, hormone-sensitive lipase (HSL). This 82 to 88 kDa protein is regulated by reversible phosphorylation. Protein kinase A activates and phosphorylates the enzyme at 2 sites, and 3 phosphatases have been implicated in HSL dephosphorylation. The translocation of HSL from the cytosol to the lipid droplet in response to lipolytic stimulation may be facilitated by a family of lipid-associated droplets called perilipins that are heavily phosphorylated by protein kinase A and dephosphorylated by insulin. As the mechanisms regulating adipocyte lipolysis continue to be uncovered, we look forward to the challenges of integrating these findings with research at the in situ and in vivo levels.
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PMID:Mechanisms regulating adipocyte lipolysis. 978 23

To determine the effects of food restriction and leptin administration on several transcripts involved in energy homeostasis, we examined leptin, uncoupling proteins (UCP) 1, 2 and 3, lipoprotein lipase (LPL), beta3-adrenergic receptors (beta3AR) and hormone-sensitive lipase (HSL) mRNA levels in brown adipose tissue (BAT) and epididymal (EWAT) and perirenal (PWAT) white adipose tissue in three groups of rats. The groups were administered leptin for 1 week, or had food restricted to the amount of food consumed by the leptin-treated animals, or had free access to food. Leptin administration increased serum leptin concentrations 50-fold and decreased food consumption by 43%, whereas serum insulin and corticosterone concentrations were unchanged. Leptin increased LPL mRNA by 80%, UCP1 mRNA twofold, and UCP3 mRNA levels by 62% in BAT, and increased UCP2 mRNA levels twofold in EWAT. In contrast, UCP2 mRNA levels were unchanged in PWAT and BAT. In WAT from food-restricted rats, leptin gene expression was diminished by 40% compared with those fed ad libitum. With leptin administration, there was a further 50% decrease in leptin expression. LPL mRNA levels were decreased by food restriction but not by leptin in WAT, whereas beta3AR and HSL mRNA levels were unchanged with either food restriction or leptin treatment. The present study indicates that leptin increases the gene expression of UCP2 in EWAT and that of UCP1, UCP3 and LPL in BAT, whereas reduced food consumption but not leptin, decreases LPL expression in WAT. In addition, with leptin administration there is a decrease in leptin gene expression in WAT, independent of food intake and serum insulin and corticosterone concentrations.
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PMID:UCP2, UCP3 and leptin gene expression: modulation by food restriction and leptin. 979 77

The aim of this study was to investigate the effect of aerobic exercise training on the lipolytic response of adipose tissue in obese subjects. Thirteen men (body mass index = 36.9 +/- 1.3 kg/m2) were submitted to aerobic physical training on a cycloergometer (30-45 min, 4 days a wk) for 3 mo. Adipocyte sensitivity to the action of catecholamines and insulin was studied in vitro before and after training. Training induced a decrease in the percentage of fat mass (P < 0.05) without changing the body weight. Basal lipolysis and hormone-sensitive lipase activity were significantly decreased after training (P < 0.05). The lipolytic effects of epinephrine, isoprenaline (beta-adrenoceptor agonist), and dobutamine (beta1-adrenoceptor agonist) were significantly increased (P < 0.05) but not those of procaterol (beta2-adrenoceptor agonist). The antilipolytic effects of alpha2-adrenoceptor and insulin were significantly decreased (P < 0.05). Lipolysis stimulation by agents acting at the postreceptor level was unchanged after training. In conclusion, aerobic physical training in obese male subjects modifies adipose tissue lipolysis through an enhancement of beta-adrenergic response and a concomitant blunting of adipocyte antilipolytic activity.
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PMID:Endurance training changes in lipolytic responsiveness of obese adipose tissue. 984 36


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