Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 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

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

Adipocyte hormone leptin (OB protein) is considered to be an "adiposity signal" regulating body weight homeostasis and energy balance. We have previously reported that oestrogens (oestradiol-benzoate) significantly decrease the body weight in male rats, increase anterior pituitary and serum levels of the intracellular messenger cAMP, which activates cAMP-dependent protein kinase A, their targets include hormone-sensitive lipase and they influence the brain sympathetic system. The present study tested our hypothesis that oestrogens could influence serum leptin levels in male mice. We found that chronic administration of oestradiol-benzoate significantly attenuated serum levels of leptin, in the dependence on the duration of its administration, and simultaneously decreased body weight. We suppose that oestrogens affect leptin levels interacting with the signal transmission system of cAMP, possibly at the genome level. Our observations that the food consumption of mice with simultaneously decreased body weight and levels of serum leptin support the idea that there exists a satiety factor that counters the effect of low leptin.
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PMID:The decrease of serum leptin levels in oestrogen-treated male mice. 972 95

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

Because the enzymatic regulation of muscle triglyceride metabolism is poorly understood we explored the character and activation of neutral lipase in muscle. Western blotting of isolated rat muscle fibers demonstrated expression of hormone-sensitive lipase (HSL). In incubated soleus muscle epinephrine increased neutral lipase activity by beta-adrenergic mechanisms involving cyclic AMP-dependent protein kinase (PKA). The increase was paralleled by an increase in glycogen phosphorylase activity and could be abolished by antiserum against HSL. Electrical stimulation caused a transient increase in activity of both neutral lipase and glycogen phosphorylase. The increase in lipase activity during contractions was not influenced by sympathectomy or propranolol. Training diminished the epinephrine induced lipase activation in muscle but enhanced the activation as well as the overall concentration of lipase in adipose tissue. In agreement with the in vitro findings, in adrenalectomized patients an increase in muscle neutral lipase activity was found at the end of prolonged exercise only if epinephrine was infused. In accordance with feedforward regulation of substrate mobilization in exercise, our studies have shown that HSL is present in skeletal muscle cells and is stimulated in parallel with glycogen phosphorylase by both epinephrine and contractions. HSL adapts differently to training in muscle compared with adipose tissue.
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PMID:Hormone-sensitive lipase (HSL) expression and regulation in skeletal muscle. 978 28

Triglycerides in the beta-cell may be important for stimulus-secretion coupling, through provision of a lipid-derived signal, and for pathogenetic events in NIDDM, where lipids may adversely affect beta-cell function. In adipose tissues, hormone-sensitive lipase (HSL) is rate-limiting in triglyceride hydrolysis. Here, we investigated whether this enzyme is also expressed and active in beta-cells. Northern blot analysis and reverse transcription-polymerase chain reaction demonstrated that HSL is expressed in rat islets and in the clonal beta-cell lines INS-1, RINm5F, and HIT-T15. Western blot analysis identified HSL in mouse and rat islets and the clonal beta-cells. In mouse and rat, immunocytochemistry showed a predominant occurrence of HSL in beta-cells, with a presumed cytoplasmic localization. Lipase activity in homogenates of the rodent islets and clonal beta-cells constituted 2.1 +/- 0.6% of that in adipocytes; this activity was immunoinhibited by use of antibodies to HSL. The established HSL expression and activity in beta-cells offer a mechanism whereby lipids are mobilized from intracellular stores. Because HSL in adipocytes is activated by cAMP-dependent protein kinase (PKA), PKA-regulated triglyceride hydrolysis in beta-cells may participate in the regulation of insulin secretion, possibly by providing a lipid-derived signal, e.g., long-chain acyl-CoA and diacylglycerol.
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PMID:Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells. 989 50

GH, in the presence of glucocorticoid, produces a delayed increase in lipolysis in rat adipose tissue, but the biochemical mechanisms that account for this action have not been established. Other lipolytic agents rapidly activate adenylyl cyclase (AC) and the resulting production of cAMP initiates a chain of reactions that culminates in the activation of hormone-sensitive lipase. We compared responses of segments of rat epididymal fat or isolated adipocytes to 30 ng/ml GH and 0.1 microg/ml dexamethasone (Dex) with 0.1 ng/ml isoproterenol (ISO), which evoked a similar increase in lipolysis. All measurements were made during the fourth hour after the addition of GH+Dex or immediately after the addition of ISO to cells or tissues that had been preincubated for 3 h without hormone. Although no significant increases in cAMP were discernible in homogenates of GH+Dex-treated tissues, Rp-cAMPS (Rp-adenosine 3'5'-phosphothioate), a competitive inhibitor of cAMP, was equally effective in decreasing lipolysis induced by GH+Dex or ISO. The proportion of PKA that was present in the active form was determined by measuring the incorporation of 32P from [gamma-32P]ATP into kemptide in the absence and presence of saturating amounts of cAMP. GH+Dex and ISO produced similar increases in protein kinase A activity in tissue extracts. Treatment with GH+Dex did not change the total forskolin-stimulated AC present in either a crude membrane pellet sedimented at 16K x g or a less dense membrane pellet sedimented at 100K x g, but doubled the AC activity in the 16K pellet when assayed in the absence of forskolin. To evaluate possible effects on G proteins, pellets obtained from centrifugation of adipocyte homogenates at 16K x g and 100K x g were solubilized and subjected to PAGE and Western analysis. GH+Dex decreased Gi alpha2 by 44% (P < 0.02) in the 16K pellets and increased it by 52% (P < 0.01) in the 100K pellets. Gs alpha in the 16K pellet was unaffected by GH+Dex and was decreased (P < 0.05) in the 100K pellet. Sucrose density fractionation of the 16K pellets revealed a similar GH+Dex-dependent shift of Gi alpha2 to less dense fractions as determined by both Western analysis and [32P]NAD ribosylation catalyzed by pertussis toxin. No such changes were seen in the distribution of Gs alpha or 5'-nucleotidase. Colchicine (100 microM) blocked the GH+Dex-dependent shift of Gi alpha2 from the 16K to the 100K pellet and blocked the lipolytic effects of GH+Dex, but not those of ISO. We conclude that by modifying the relationship between AC and Gi alpha2, GH+Dex relieves some inhibition of cAMP production and consequently increases lipolysis.
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PMID:Growth hormone and dexamethasone stimulate lipolysis and activate adenylyl cyclase in rat adipocytes by selectively shifting Gi alpha2 to lower density membrane fractions. 1006 47

The enzymic regulation of triacylglycerol breakdown in skeletal muscle is poorly understood. Western blotting of muscle fibres isolated by collagenase treatment or after freeze-drying demonstrated the presence of immunoreactive hormone-sensitive lipase (HSL), with the concentrations in soleus and diaphragm being more than four times the concentrations in extensor digitorum longus and epitrochlearis muscles. Neutral lipase activity determined under conditions optimal for HSL varied directly with immunoreactivity. Expressed relative to triacylglycerol content, neutral lipase activity in soleus muscle was about 10 times that in epididymal adipose tissue. In incubated soleus muscle, both neutral lipase activity against triacylglycerol (but not against a diacylglycerol analogue) and glycogen phosphorylase activity increased in response to adrenaline (epinephrine). The lipase activation was completely inhibited by anti-HSL antibody and by propranolol. The effect of adrenaline could be mimicked by incubation of crude supernatant from control muscle with the catalytic subunit of cAMP-dependent protein kinase, while no effect of the kinase subunit was seen with supernatant from adrenaline-treated muscle. The results indicate that HSL is present in skeletal muscle and is stimulated by adrenaline via beta-adrenergic activation of cAMP-dependent protein kinase. The concentration of HSL is higher in oxidative than in glycolytic muscle, and the enzyme is activated in parallel with glycogen phosphorylase.
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PMID:Expression of hormone-sensitive lipase and its regulation by adrenaline in skeletal muscle. 1033 90

Thermal injury causes a hypermetabolic state associated with increased levels of catabolic hormones, but the molecular bases for the metabolic abnormalities are poorly understood. We investigated the lipolytic responses after beta(3)-adrenoceptor (beta(3)-AR) agonists and evaluated the associated changes in beta-AR and its downstream signaling molecules in adipocytes isolated from rats with thermal injury. Maximal lipolytic responses to a specific beta(3)-AR agonist, BRL-37344, were significantly attenuated at post burn days (PBD) 3 and 7. Despite significant reduction of the cell surface beta(3)-AR number and its mRNA at PBD 3 and 7, BRL-37344 and forskolin-stimulated cAMP levels were not decreased. Glycerol production in response to dibutyryl cAMP, a direct stimulant of hormone-sensitive lipase (HSL) via protein kinase A (PKA), was significantly attenuated. Although immunoblot analysis indicated no differences in the expression and activity of PKA or in the expression of HSL, HSL activity showed significant reductions. Finally, beta(3)-AR-induced insulin secretion was indeed attenuated in vivo. These studies indicate that the beta(3)-AR system is desensitized after burns, both in the adipocytes and in beta(3)-AR-induced secretion of insulin. Furthermore, these data suggest a complex and unique mechanism underlying the altered signaling of lipolysis at the level of HSL in animals after burns.
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PMID:A unique mechanism of desensitization to lipolysis mediated by beta(3)-adrenoceptor in rats with thermal injury. 1044 28

Lipotransin is a novel hormone-sensitive lipase (HSL)-interacting protein that appears to translocate HSL to the lipid droplet. The interaction of the two proteins depends upon the phosphorylation of HSL by protein kinase A. Once formed, the complex is dissociated by ATP hydrolysis, due to the ATPase activity of lipotransin. In 3T3L1 adipocytes, insulin produces a stable complex between the proteins, due to a modification of lipotransin. Thus, lipotransin is a novel docking protein that may direct the hormonally regulated redistribution of hormone-sensitive lipase.
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PMID:Lipotransin: a novel docking protein for hormone-sensitive lipase. 1044 32


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