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PubMed2006

Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome.

Adipose tissue lipolysis is the catabolic process leading to the breakdown of triglycerides stored in fat cells and release of fatty acids and glycerol. Recent work has revealed that lipolysis is not a simple metabolic pathway stimulated by catecholamines and inhibited by insulin. There have been new discoveries on the endocrine and paracrine regulation of lipolysis and on the molecular mechanisms of triglyceride hydrolysis. Catecholamines modulate lipolysis through lipolytic beta-adrenoceptor and antilipolytic alpha2-adrenoceptor. Recent studies have allowed a better understanding of the relative contribution of the two types of receptors and provided evidence for the in vivo involvement of alpha2-adrenoceptors in the physiological control of subcutaneous adipose tissue lipolysis. A puzzling observation is the characterization of a residual catecholamine-induced lipolysis in mice deficient in beta-adrenoceptors. A novel lipolytic system has been characterized in human fat cells. Natriuretic peptides stimulate lipolysis through a cGMP-dependent pathway. There are other lipolytic pathways active in human fat cells which importance is not fully understood. Forty years after the description of the antilipolytic effect of nicotinic acid, the receptors have been identified. Adrenomedullin which is produced by adipocytes exert an antilipolytic effect through an indirect mechanism involving nitric oxide. The molecular details of the lipolytic reaction are not fully understood. The role of the lipases has been re-evaluated with the cloning of adipose triglyceride lipase. Hormone-sensitive lipase appears as the major lipase for catecholamine and natriuretic peptide-stimulated lipolysis whereas adipose triglyceride lipase mediates the hydrolysis of triglycerides during basal lipolysis. Translocation of hormone-sensitive lipase bound to the adipocyte lipid binding protein to the lipid droplet seems to be an important step during lipolytic activation. Re-organization of the lipid droplet coating by perilipins facilitates the access of the enzyme. The role of other lipid-interacting proteins in lipolysis is still unclear. The proteins involved in the lipolytic process constitute drug targets for the treatment of obesity and the metabolic syndrome. The oldest example is nicotinic acid (niacin) used as a hypolipidaemic drug. A first approach consists in molecules stimulating lipolysis and oxidation of the released fatty acids to decrease fat stores. A second approach is a chronic inhibition of lipolysis to diminish plasma fatty acid level which is a central feature of the metabolic syndrome.

Adipose Tissue↗
PubMed1992

Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin-1, and the interferons is blocked by inhibition of prostaglandin synthesis.

Multiple cytokines induce a number of alterations in lipid metabolism which can produce hyperlipidemia. Recent studies have demonstrated that tumor necrosis factor (TNF) increases lipolysis, resulting in an increase in circulating FFA levels, which stimulates hepatic triglyceride production, thereby contributing to the hyperlipidemia induced by TNF. In the present investigation we have determined the effects of a variety of cytokines on lipolysis in cultured 3T3-F442A adipocytes. TNF increased lipolysis approximately 3-fold with a maximal effect at 100 ng/ml and a half-maximal increase at 5-10 ng/ml. This increase was first observed 8 h after incubation with TNF. Interleukin-1 (IL-1) and interferon-alpha (IFN), -beta, and -gamma also stimulated lipolysis in cultured adipocytes. The half-maximal increase in lipolysis occurred at approximately 10 ng/ml IL-1, 5 ng/ml IFN alpha, 10 ng/ml IFN beta, and 8 ng/ml of IFN gamma. Maximal lipolysis was observed at approximately 100 ng/ml for each of these cytokines, with the exception of IFN beta, for which maximal stimulation was observed at 1000 ng/ml. Neither platelet-activating factor nor IL-6 stimulated lipolysis; therefore, it is unlikely that these compounds mediate the increase in lipolysis induced by cytokines. However, indomethacin, a well known inhibitor of prostaglandin synthesis, prevented the increase in lipolysis induced by TNF, IL-1, IFN alpha, IFN beta, or IFN gamma. Indomethacin did not affect basal lipolysis or the acute stimulation of lipolysis induced by epinephrine. These results demonstrate that multiple cytokines can increase lipolysis and that this increase is mediated by cytokine-induced stimulation of prostaglandin synthesis.

3T3 Cells↗
PubMed1994

Triiodothyronine attenuates somatostatin inhibition of broiler adipocyte lipolysis.

A study with broiler adipocytes in culture was undertaken to determine whether triiodothyronine (T3) potentiates lipolysis by increasing glucagon binding, by attenuating inhibition of lipolysis, or both. Fat cells isolated from abdominal fat were preincubated with T3 for .5 to 24 h before removal of T3 by washing and measurement of lipolysis. Preincubation of adipocytes with T3 enhanced (P < .05) basal as well as glucagon-stimulated lipolysis in a dose-response and time-dependent manner. Enhancement of lipolysis was maximal in the presence of 15 to 150 nM T3. Potentiation of lipolysis by 150 nM T3 was evident at 4 and 24 h but not at .5 h of pretreatment. Overall, T3 enhancement of lipolysis stimulated by submaximal doses of glucagon was similar in magnitude to enhancement of lipolysis stimulated by a maximal dose of glucagon but was greater (P < .05) than its enhancement of basal lipolysis. Pretreatment of adipocytes with T3 did not alter (P > .05) binding of 125I-glucagon to cell-surface receptors. When fat cells were preincubated with 150 nM T3 for 24 h, the ability of somatostatin to inhibit basal and glucagon-stimulated lipolysis was reduced (P < .05). Thus, prolonged exposure of adipocytes to T3 did not increase lipolytic sensitivity to glucagon or binding of glucagon to cell-surface receptors. However, T3-treated adipocytes exhibited enhanced basal lipolysis, enhanced lipolytic responsiveness to glucagon, and attenuated inhibition of lipolysis by somatostatin.

Adipocytes↗
PubMed1976

Effect of gemfibrozil in vitro on fat-mobilizing lipolysis in human adipose tissue.

Fat-mobilizing lipolysis was studied in rat and human adipose tissue during incubation in vitro by following the release of glycerol into the incubation medium. Gemfibrozil as well as clofibrate consistently and readily inhibited basal as well as noradrenaline-stimulated fat-mobilizing lipolysis in rat fat. With human adipose tissue no effect was observed with gemfibrozil and clofibrate on basal lipolysis. This may be due to the comparatively low rate of the nonstimulated fat-mobilizing lipolysis in human tissue incubated in vitro. When lipolysis was stimulated with noradrenaline as well as isoprenaline, however, both gemfibrozil and clofibrate significantly reduced the fat-mobilizing lipolysis. This inhibition of lipolysis was however not observed in all studies. When lipolysis had been stimulated with theophylline, no inhibition of lipolysis was obtained with either compound. The possibility that reduced fat-mobilizing lipolysis in adipose tissue may cause a lowering of plasma triglycerides by reducing the flow of FFA to the liver is discussed in some detail. It is also suggested that inhibition of lipolysis may be accompanied by increased activity of lipoprotein lipase as well as an increase in the FIAT process. However, the pharmacological implication of the above-mentioned findings, particularly for gemfibrozil, must await further studies, as fairly large doses, around 1 mg/ml of incubation medium, were needed to obtain inhibition of fat-mobilizing lipolysis.

Adipose Tissue↗
PubMed2006

Calyculin and okadaic acid promote perilipin phosphorylation and increase lipolysis in primary rat adipocytes.

Lipolysis is primarily regulated by protein kinase A (PKA), which phosphorylates perilipin and hormone-sensitive lipase (HSL), and causes translocation of HSL from cytosol to lipid droplets in adipocytes. Perilipin coats lipid droplet surface and assumes to prevent lipase access to triacylglycerols, thus inhibiting basal lipolysis; phosphorylated perilipin facilitates lipolysis on PKA activation. Here, we induced lipolysis in primary rat adipocytes by inhibiting protein serine/threonine phosphatase with specific inhibitors, okadaic acid and calyculin. The incubation with calyculin promotes incorporation of 32Pi into perilipins, thus, confirming that perilipin is hyperphosphorylated. The lipolysis response to calyculin is gradually accompanied by increased accumulation of phosphorylated perilipin A in a concentration- and time-responsive manner. When perilipin phosphorylation is abrogated by the addition of N-ethylmaleimide, lipolysis ceases. Different from a considerable translocation of HSL upon PKA activation with isoproterenol, calyculin does not alter HSL redistribution in primary or differentiated adipocytes, as confirmed by both immunostaining and immunoblotting. Thus, we suggest that inhibition of the phosphatase by calyculin activates lipolysis via promoting perilipin phosphorylation rather than eliciting HSL translocation in adipocytes. Further, we show that when the endogenous phosphatase is inhibited by calyculin, simultaneous PKA activation with isoproterenol converts most of the perilipin to the hyperphosphorylated species, and induces enhanced lipolysis. Apparently, as PKA phosphorylates perilipin and stimulates lipolysis, the phosphatase acts to dephosphorylate perilipin and attenuate lipolysis. This suggests a two-step strategy governed by a kinase and a phosphatase to modulate the steady state of perilipin phosphorylation and hence the lipolysis response to hormonal stimulation.

Adipocytes↗
PubMed1990

Influence of exogenous fatty acids and ketone bodies on rates of lipolysis in isolated ventricular myocytes from normal and diabetic rats.

The effect of oleate (0.3 and 1.2 mM) and the combined effect of beta-hydroxybutyrate (4 and 8 mM) and acetoacetate (1 and 2 mM) on rates of lipolysis (glycerol output) was determined with calcium-tolerant myocytes isolated from the hearts of normal rats and hearts from acutely (2-3 days; 100 mg/kg streptozotocin) diabetic rats. In addition, the effect of these exogenous substrates on rates of lipolysis was investigated in triacylglycerol (TG) loaded myocytes prepared from normal hearts by inclusion of oleate in the isolation solutions. Diabetic and TG-loaded myocytes had higher lipolytic rates than normal myocytes. In control myocytes, oleate (1.2 mM) did not affect basal lipolysis, but it reduced isoproterenol-stimulated lipolysis by 30%. In diabetic and TG-loaded myocytes, the addition of 1.2 mM oleate inhibited basal rates of lipolysis by 41 and 40%, respectively, and isoproterenol-stimulated rates of lipolysis by 43 and 53%, respectively. However, lipolytic rates measured in the presence of 1.2 mM oleate with diabetic and TG-loaded myocytes were still higher than lipolysis in normal myocytes incubated in the absence of oleate. Ketone bodies increased both basal and isoproterenol-stimulated lipolysis in normal myocytes. In diabetic myocytes, ketone bodies produced a modest stimulation of basal lipolysis but had no effect on isoproterenol-stimulated rates of lipolysis. These data indicate that mobilization of endogenous TG may play an important role in supplying energy to the heart in the diabetic state. Moreover, accumulation of endogenous TG in diabetic myocardium can only partly be explained by inhibition of lipolysis by exogenous substrates.

Animals↗
PubMed1990

Evidence for a role of protein kinase C in the stimulation of lipolysis by growth hormone and isoproterenol.

The mechanism that underlies activation of lipolysis by GH is not yet understood. Although cAMP is thought to be involved, the biochemical linkages between GH and cAMP are unknown, and lipolysis produced by GH differs from that produced by such typical activators of adenylate cyclase as the catecholamines with regard to time course, maximum response, and dependence on other factors such as glucocorticoids or theophylline. The present studies were undertaken to evaluate the possibility that activation of protein kinase C by GH may play an important role in the production of the delayed increase in lipolysis. Phorbol myristate acetate (PMA), a known activator of protein kinase C, increased lipolysis in segments of adipose tissue of hypophysectomized rats, and, as with GH, this effect was potentiated by theophylline. The lipolytic effects of PMA were concentration-dependent, required a shorter lag period than those of human GH, increased as the concentration of PMA was raised from 0.1 to 10 microM, and were additive at all concentrations with lipolysis produced by saturating concentrations of GH. The lipolytic actions of GH, but not PMA, were potentiated by dexamethasone in adipose tissue of normal rats. Sphingosine and staurosporine, which are known to inhibit protein kinase C, blocked the lipolytic effects of PMA and severely reduced lipolysis in response to GH in tissues of both normal and hypophysectomized rats. Although higher concentrations of sphingosine interfered with the specific binding of 125I-labeled human GH to isolated adipocytes, the inhibitory effects of sphingosine cannot be attributed to interference with GH binding, since it decreased lipolysis by at least 50% when used at concentrations that were too low to reduce binding significantly. Staurosporine produced little (approximately 20%) or no decrease in binding. At concentrations that severely reduced lipolysis in response to GH and dexamethasone, sphingosine had little or no effect on lipolysis in response to dibutyryl cAMP or forskolin. Staurosporine and sphingosine, however, severely inhibited lipolysis in response to isoproterenol. We conclude that protein kinase C activity plays an important role in hormone-stimulated lipolysis probably by an action exerted on the transduction pathway proximal to cAMP. The present data are equally consistent with the possibilities that GH and/or isoproterenol activate protein kinase C, or that protein kinase C is constitutively active to some extent. It is likely that protein kinase C activity is permissive for, rather than a mediator of, the lipolytic actions of GH and isoproterenol.

Adipose Tissue↗
PubMed2005

Human fat cell lipolysis: biochemistry, regulation and clinical role.

Release of fatty acids (FAs) from adipose tissue through lipolysis in fat cells is a key event in many processes. FAs are not only energy substrates but also signalling molecules and substrates for lipoprotein production by the liver. Fat cells consist of>95% triglycerides that are hydrolysed during lipolysis to glycerol and FAs. The major rate-limiting factor for lipolysis is hormone-sensitive lipase, but additional lipases such as adipose tissue triglyceride lipase may also play a role. The regulation of human fat cell lipolysis is, in many ways, species unique. Only catecholamines, insulin and natriuretic peptides have pronounced acute effects. Catecholamines influence lipolysis through four different adrenoceptor subtypes, in contrast to rodents where only one subtype (beta(3)) is of major importance. There are regional variations in adipocyte lipolysis leading to more release of FAs from the visceral than subcutaneous adipose tissue during hormone stimulation (insulin, catecholamines). Since, only visceral fat is linked to the liver (by the portal vein), alterations in visceral adipocyte tissue lipolysis have direct effects on the liver through portal FA release. The regional variations in lipolysis are further enhanced in obesity and polycystic ovarian syndrome, and are of importance for dyslipidaemia, hyperinsulinaemia and glucose intolerance in these conditions. There is a marked elevation of circulating FA levels among the obese, which may be due to enhanced production of tumour necrosis factor alpha in adipose tissue. This cytokine stimulates lipolysis through so-called MAP kinases. Pharmacological agents in clinical practice such as nicotinic acid and glitazones exert lipid-lowering and glucose-lowering effects, respectively, by decreasing FA output from the adipose tissue. This review covers the biochemistry, regulation and clinical aspects of human fat cell lipolysis.

Adipocytes↗
PubMed1999

W-5 and quin 2-AM reverse the inhibitory effect of insulin on lipolysis due to dibutyryl cAMP.

The effects of W-5, a weak calmodulin antagonist, and quin 2-AM, a cell permeant calcium chelator, on lipolysis and antilipolytic activity of insulin were studied in isolated rat adipocytes. We have previously shown that W-7, a strong calmodulin antagonist, suppresses the inhibitory effect of insulin on lipolysis due to dibutyryl cAMP (Bt2cAMP) in a dose-dependent manner [H. Goko, A. Matsuoka, Diabetes Res. Clin. Prac. 19 (1993) 177-181] and verapamil, a calcium antagonist, potentiates lipolysis due to Bt2cAMP. Like W-7, W-5 suppressed the antilipolytic action of insulin on lipolysis due to Bt2cAMP in a dose-dependent manner. However, when lipolysis was potentiated with 3-isobutyryl-1-methylxanthine (IBMX), W-5 did not suppress the antilipolytic action of insulin. At the same time, like verapamil, W-5 also potentiated lipolysis due to Bt2cAMP in a dose-dependent manner. Thus W-5 has the pharmaceutical effects of both W-7 and verapamil. The chelation of intracellular Ca2+ in adipocytes with quin 2-AM also produced a dose-dependent potentiation of lipolysis due to Bt2cAMP and suppression of the antilipolytic action of insulin on lipolysis due to Bt2cAMP. These effects of quin 2-AM are the same as those of W-5. Therefore, our results suggest that the cytoplasmic Ca2+ plays a pivotal role in mediating the potentiation of lipolysis and antilipolytic action of insulin when lipolysis is induced by Bt2cAMP in rat adipocytes and that W-5 appears to exert its pharmaceutical effects through the inhibition of intracellular calcium-dependent steps other than calmodulin.

Adipocytes↗
PubMed2005

On the suppression of plasma nonesterified fatty acids by insulin during enhanced intravascular lipolysis in humans.

During the fasting state, insulin reduces nonesterified fatty acid (NEFA) appearance in the systemic circulation mostly by suppressing intracellular lipolysis in the adipose tissue. In the postprandial state, insulin may also control NEFA appearance through enhanced trapping into the adipose tissue of NEFA derived from intravascular triglyceride lipolysis. To determine the contribution of suppression of intracellular lipolysis in the modulation of plasma NEFA metabolism by insulin during enhanced intravascular triglyceride lipolysis, 10 healthy nonobese subjects underwent pancreatic clamps at fasting vs. high physiological insulin level with intravenous infusion of heparin plus Intralipid. Nicotinic acid was administered orally during the last 2 h of each 4-h clamp to inhibit intracellular lipolysis and assess insulin's effect on plasma NEFA metabolism independently of its effect on intracellular lipolysis. Stable isotope tracers of palmitate, acetate, and glycerol were used to assess plasma NEFA metabolism and total triglyceride lipolysis in each participant. The glycerol appearance rate was similar during fasting vs. high insulin level, but plasma NEFA levels were significantly lowered by insulin. Nicotinic acid significantly blunted the insulin-mediated suppression of plasma palmitate appearance and oxidation rates by approximately 60 and approximately 70%, respectively. In contrast, nicotinic acid did not affect the marked stimulation of palmitate clearance by insulin. Thus most of the insulin-mediated reduction of plasma NEFA appearance and oxidation can be explained by suppression of intracellular lipolysis during enhanced intravascular triglyceride lipolysis in healthy humans. Our results also suggest that insulin may affect plasma NEFA clearance independently of the suppression of intracellular lipolysis.

Adult↗
PubMed2004

The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis.

This study assessed the effects of selective inhibitors of 3',5'-cyclic nucleotide phosphodiesterases (PDEs) on adipocyte lipolysis. IC224, a selective inhibitor of type 1 phosphodiesterase (PDE1), suppressed lipolysis in murine 3T3-L1 adipocytes (69.6 +/- 5.4% of vehicle control) but had no effect in human adipocytes. IC933, a selective inhibitor of PDE2, had no effect on lipolysis in either cultured murine 3T3-L1 adipocytes or human adipocytes. Inhibition of PDE3 with cilostamide moderately stimulated lipolysis in murine 3T3-L1 and rat adipocytes (397 +/- 25% and 235 +/- 26% of control, respectively) and markedly stimulated lipolysis in human adipocytes (932 +/- 7.6% of control). Inhibition of PDE4 with rolipram moderately stimulated lipolysis in murine 3T3-L1 adipocytes (291 +/- 13% of control) and weakly stimulated lipolysis in rat adipocytes (149 +/- 7.0% of control) but had no effect on lipolysis in human adipocytes. Cultured adipocytes also responded differently to a combination of PDE3 and PDE4 inhibitors. Simultaneous exposure to cilostamide and rolipram had a synergistic effect on lipolysis in murine 3T3-L1 and rat adipocytes but not in human adipocytes. Hence, the relative importance of PDE3 and PDE4 in regulating lipolysis differed in cultured murine, rat, and human adipocytes.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

Prolonged in vitro exposure of broiler adipocytes to somatostatin enhances lipolysis and induces desensitization of antilipolysis.

Adipocytes isolated from abdominal fat of female broilers and maintained in primary culture were used to characterize acute and chronic effects of somatostatin (SRIF) on lipolysis and antilipolysis and to determine whether desensitization and cross-regulation phenomena are involved in the regulation of adipocyte metabolism by SRIF and glucagon. Acute exposure of adipocytes to SRIF resulted in a dose-dependent inhibition of basal and glucagon-stimulated lipolysis. The potency and extent of lipolysis inhibition by SRIF were inversely related to the dose of glucagon used to stimulate lipolysis. Preincubation of adipocytes with SRIF induced a dose-response and time-dependent increase in the set-point of lipolysis. Adipocyte sensitivity to glucagon was not altered by SRIF pretreatment. In contrast, preincubation with SRIF reduced adipocyte sensitivity and maximal responsiveness to SRIF. The pattern and extent of antilipolysis attenuation were dependent on the dose and time of preincubation with SRIF as well as on the concentration of glucagon used to acutely stimulate lipolysis. In two experiments, the attenuation of antilipolysis induced by SRIF pretreatment was observed in the absence of enhanced lipolysis, whereas in one experiment enhanced lipolysis was observed in the absence of attenuated antilipolysis. These results indicated that persistent activation of antilipolysis by SRIF increased the set-point of lipolysis by sensitizing (i.e., cross-regulating) lipolysis and by desensitizing antilipolysis.

Adipose Tissue↗
PubMed1992

Relationship between cyclic AMP production and lipolysis induced by forskolin in rat fat cells.

Forskolin (7 beta-acetoxy-8, 13-epoxy-1 alpha,6 beta,9 alpha-trihydroxy-labd-14-ene-11-one) induced both cyclic AMP production and lipolysis in intact fat cells, but stimulated lipolysis without increasing cyclic AMP at a concentration of 10(-5) M. Homogenization of fat cells elicited lipolysis without elevation of cyclic AMP. Forskolin did not stimulate lipolysis in the homogenate. Forskolin stimulated both cyclic AMP production and lipolysis in a cell-free system consisting of endogenous lipid droplets and a lipoprotein lipase-free lipase fraction prepared from fat cells. However, at a concentration of 10(-6) M, it induced lipolysis without increase in the cyclic AMP content in this cell-free system. In the cell-free system, homogenization of the lipid droplets resulted in marked increase in lipolysis to almost the same level as that with 10(-4) M forskolin without concomitant increase in cyclic AMP. Addition of forskolin to a cell-free system consisting of homogenized lipid droplets and lipase did not stimulate lipolysis further. Phosphodiesterase activities were found to be almost the same both in the presence and absence of forskolin in these reaction mixtures. Although 10(-3) M forskolin produced maximal concentrations of cyclic AMP: 6.7 x 10(-7) M in fat cells and 2.7 x 10(-7) M in the cell-free system, 10(-4) M cyclic AMP did not stimulate lipolysis in the cell-free system. In a cell-free system consisting of lipid droplets and the lipase, pyrophosphate inhibited forskolin-induced cyclic AMP production, but decreased forskolin-mediated lipolysis only slightly. Based on these results, mechanism of lipolytic action of forskolin was discussed.

Adipose Tissue↗
PubMed1989

Effects of adenosine and pertussis toxin on lipolysis in adipocytes from exercise-trained male rats.

The sensitivity and responsiveness of adipocyte lipolysis to adenosine and pertussis toxin were studied in exercise-trained male rats. Exercise training (9 weeks of treadmill running) significantly increased lipolytic response of adipocytes to noradrenaline (NA). Addition of adenosine deaminase (ADA) to reaction mixture effectively enhanced NA-stimulated lipolysis in adipocytes from both conditioned rats. However, under these conditions, the difference due to exercise training was still evident, although the difference was less pronounced. The inhibition curves of the R-site adenosine analogue N6-phenylisopropyladenosine (PIA) against "basal" (lipolysis in the presence of ADA) and NA-stimulated lipolysis were almost comparable between two groups. Only a small (approx. 2-fold) increase in IC50 of adipocyte lipolysis was observed in each inhibition curve in exercise-trained rats. Within 120 min of addition of pertussis toxin to adipocytes from control rats, "basal" lipolysis was significantly increased as compared to "basal" lipolysis in the absence of toxin at the same point. Similarly, pertussis toxin significantly increased "basal" lipolysis in exercise-trained adipocytes. However these were relatively sensitive to pertussis toxin, since significant effect of toxin was seen within 60 min. An addition of NA (0.1 uM) to the medium in the presence of ADA and toxin significantly increased adipocyte lipolysis in both conditioned rats. Again, under these conditions, we observed that the maximal rate of lipolysis of adipocytes from exercise-trained rats was increased as compared to control rats. These results suggest that the decreased input through the inhibitory pathway in lipolytic cascade may be not rate limiting for the amplified lipolytic responsiveness of adipocytes to hormonal stimuli in exercise-trained rats.

Adenosine↗
PubMed1983

[Effects of Ca2+ and calmodulin inhibitors on lipolysis induced by epinephrine, norepinephrine, caffeine and ACTH in rat epididymal adipose tissue].

The effects of Ca2+ and calmodulin inhibitors on lipolysis induced by epinephrine, norepinephrine, caffeine and ACTH in rat epididymal adipose tissue were investigated. 1. Omission of Ca2+ from the incubation medium slightly depressed lipolysis induced by epinephrine, norepinephrine and ACTH. Lipolysis induced by caffeine was significantly depressed. 2. Lipolysis induced by epinephrine, norepinephrine, caffeine and ACTH was strongly depressed when Ca2+-deficient tissue was incubated in Ca2+-free Ringer solution. 3. In Ca2+-deficient tissue, the addition of 0.75mM Ca2+ apparently restored lipolysis induced by epinephrine, norepinephrine and ACTH, whereas that by caffeine was restored to only approximately 89%. 4. The addition of La3+ markedly inhibited lipolysis induced by each agonist. 5. The Ca2+ antagonists such as verapamil and diltiazem dose-dependently inhibited lipolysis induced by each agonist. 6. The specific calmodulin inhibitors such as chlorpromazine, trifluoperazine and W-7 markedly inhibited lipolysis induced by each agonist. These results strongly support the possible key role that the redistribution and influx of Ca2+ may play in lipolysis induced by epinephrine, norepinephrine, caffeine and ACTH, and further suggest that calmodulin may affect lipolysis.

Adipose Tissue↗
PubMed2006

Protein kinase C attenuates beta-adrenergic receptor-mediated lipolysis, probably through inhibition of the beta1-adrenergic receptor system.

Lipolysis in rat white adipocytes is stimulated by beta-adrenergic agonists. Phorbol 12-myristate 13-acetate (PMA) attenuated the receptor-mediated lipolysis by causing a shift of the dose-response curve to the higher concentrations of norepinephrine and isoproterenol. Although the adipocytes possess beta1-, beta2-, and beta3-adrenergic receptor subtypes, the effect of PMA was observed only when a beta1-agonist (dobutamine) was used. No lipolysis-attenuating effect of PMA was found when cells were exposed to a beta2-agonist (procaterol) and beta3-agonists (BRL 37344 and CL 316243), or to forskolin and 8-bromo cAMP. CGP 20712A (beta1-antagonist) efficiently inhibited lipolysis by norepinephrine, isoproterenol, and dobutamine, but did not affect lipolysis by the beta2- and beta3-agonists. ICI 118551 (beta2-antagonist) had no significant effect on lipolysis by the beta-agonists examined. CGP 20712A abolished the lipolysis-attenuating effect of PMA, but ICI 118551 did not. The protein kinase C (PKC) inhibitors, GF 109203X or Gö 6976, suppressed the effect of PMA. Pretreatment of adipocytes with PMA for 6 h caused downregulation of conventional and novel PKCs in association with a decrease in the lipolysis-attenuating effect of PMA. These results indicate that conventional and novel PKCs attenuate lipolysis mediated by beta-adrenergic receptors, probably through inhibition of the beta1-adrenergic receptor system.

Adipocytes↗
PubMed1983

New derivatives of methyl-xanthines: effect of thiocaffeine thiotheophylline and 8-phenyltheophylline on lipolysis and on phosphodiesterase activities.

The effects of some old and new methylxanthines and 6-thioxanthines, i.e. theophylline (TH), caffeine (CAFF), thiotheophyl line (S-TH), thiocaffeine (S-CAFF), 8-phenyltheophylline (8-PT), 3-isobutyl-1-methyl-xanthine (IBMX) were compared at the level of adipose tissue on spontaneous and norepinephrine-induced lipolysis as well as on fat cell phosphodiesterases. These agents stimulated lipolysis. 8-PT was the most potent; thiocaffeine and thiotheophylline the least potent; IBMX and theophylline had intermediate potencies. The order of potency of the same drugs in potentiating norepinephrine-stimulated lipolysis was: IBMX greater than 8-PT greater than S-CAFF greater than greater than S-TH greater than CAFF greater than TH. The rank order of potency to inhibit cAMP phosphodiesterases was: IBMX greater than S-TH and S-CAFF greater than TH much greater than 8-PT (uneffective). Thus (a) thiocaffeine and thiotheophylline were more potent than the parent compound theophylline in inhibiting cAMP-PDE, although their per se stimulating effect on lipolysis was much lower. This indicates that in the thioxanthines the stimulus per se on lipolysis can be dissociated from their effectiveness as inhibitors of PDE. (b) In contrast, 8-PT (a blocker of adenosine receptors) has a potent lipolytic action per se and a potentiating effect on norepinephrine-induced lipolysis, even if deprived of effect on PDE. This indicates that the potentiating power of methylxanthines on norepinephrine-stimulated lipolysis is not strictly dependent on their anti-PDE activities. These results suggest that in adipose tissue (more similar than adipocytes to the in vivo conditions) the anti-adenosine potency of methylxanthines is the prominent factor in stimulating basal lipolysis. Both anti-adenosine and anti-PDE activities are involved in modulating hormone-induced lipolysis.

Adipose Tissue↗
PubMed2000

Role of beta-adrenergic receptor subtypes in lipolysis.

In vitro lipolysis stimulated by low (-)-isoprenaline concentrations (< or =30 nM) in epididymal white adipocytes from Sprague-Dawley rats was inhibited at least 60-80% by the specific beta1-antagonists LK 204-545 and CGP 20712A (1 microM), suggesting that at these low (10 nM) concentrations of (-)-isoprenaline lipolysis was primarily (80%) but not solely mediated via beta1-adrenergic receptors. Low concentrations (100 nM) of (-)-noradrenaline and formoterol also confirmed a role for beta1-adrenergic receptors in mediating lipolysis at low concentrations of these agonists. At higher agonist concentrations, beta3-adrenergic receptors were fully activated and were the dominant beta-adrenergic receptor subtype mediating the maximum lipolytic response, and the maximum response was not affected by the beta1-antagonists, demonstrating that the beta3-receptor is capable of inducing maximum lipolysis on its own. Studies of lipolysis induced by the relatively beta2-selective agonist formoterol in the presence of beta1-blockade (1 microM CGP 20712A) demonstrated the inability of the beta2-selective antagonist ICI 118-551 to inhibit the residual lipolysis at concentrations of ICI 118-551 < or = 1 microM. Higher concentrations of ICI 118-551 inhibited the residual formoterol-induced lipolysis competetively, but with low affinity (approximately 500-fold lower than its beta2-adrenergic receptor pA2, 7.80 +/- 0.21), suggesting that formoterol was not acting via beta2-adrenergic receptors. These data are consistent with beta1-adrenergic receptors playing an important role in lipolysis at physiological but not pharmacological concentrations of catecholamines and that beta2-adrenergic receptors play no obvious direct role in mediating beta-adrenergic receptor agonist-induced lipolysis in vitro. Finally, racemic-SR 59230A, unlike the pure (S, S)-isomer (a beta3-selective antagonist), was found to be a nonselective antagonist at the three beta-adrenergic receptor subtypes, showing that the other enantiomers have different selectivity.

Adipocytes↗