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PubMed1991

Early indicators for carcinogenesis in sex-hormone-sensitive organs.

Hormones induce tumours in various target tissues in different species of laboratory animals in long-term toxicity studies. Examples of such tumours are: mammary gland tumours in beagle dogs after long-term treatment with progestogens or progestogen/oestrogen combinations; pituitary and mammary gland tumours in rats and mice after long-term treatment with oestrogens or progestogens with an oestrogenic partial effect; interstitial cell tumours in rats after chronic overstimulation by endogenous luteinising hormone; endometrial carcinomas in rats after chronic treatment with dopamine agonists. As a rule every hormone when given in excessive doses over prolonged periods can induce a tumour in the relevant target organs. Drugs or chemicals which stimulate or inhibit the endogenous hormone production of certain endocrine organs can have the same effect. Tumour induction can be a direct or indirect effect involving specific regulatory mechanisms. In general, the induction is preceded by excessive hyperplasia of the target tissue concerned or with regard to the pituitary where excess production of the stimulating hormone occurs. Tumour induction in chronic toxicity studies can usually be predicted by determining hormone levels in short-term studies. Hormones and drugs or chemicals which induce tumours when given in doses high enough to induce hyperplasia are unlikely to do so by a genotoxic mechanism.

Animals↗
PubMed2001

Androgen sensitivity related proteins in hormone-sensitive and hormone-insensitive prostate cancer cell lines treated by androgen antagonist bicalutamide.

Members of the bcl-2 gene family and endogenous inhibitors of cyclin-dependent kinases participate in the regulation of apoptosis and cell cycle in a diverse range of cell types and are implicated in the development of hormone refractory prostate cancer and resistance to anti-cancer therapy. The expression of several of these genes can be regulated by steroid hormones and related agents via their nuclear receptors. However, insufficient information considering the protein expression after the treatment by hormone antagonists is available. The aim of this study was to evaluate the expression of anti- and pro-apoptotic proteins, (Bcl-2, Bax), and to correlate this with the appearance of some nuclear receptors and cell cycle related proteins in androgen sensitive and androgen insensitive prostate cancer cell lines, LNCaP and DU-145, after the treatment by androgen antagonist bicalutamide. Our results revealed that androgen receptor (AR) expression in LNCaP cells decreased, however in DU-145 cells AR slightly increased following anti-androgen treatment. The same agent stimulated expression of p21Waf1/Cip5 and p27Kip1 in LNCaP, as well as in DU-145 cell lines. Bcl-2 level increased slightly in LNCaP cells and, in DU-145 cells was almost undetectable. Bax expression was not changed in LNCaP but significantly decreased in DU-145 cells. Similarly, retinoid X receptor beta (RXRbeta) level was significantly down regulated after 24 hours in DU-145 and also in LNCaP cells after 72 hours. These results confirm that androgen withdrawal therapy employing anti-androgens may elicit different signalling pathways in various types of prostate cancer that may be dependent on AR status and AR sensitivity.

Androgen Antagonists↗
PubMed2001

Infertility and testicular defects in hormone-sensitive lipase-deficient mice.

The 84-kDa hormone-sensitive lipase (gene designation Lipe; EC 3.1.1.3) is a cholesterol esterase and triglyceride hydrolase that functions in the release of fatty acids from adipocytes. The role of hormone-sensitive lipase in other tissues such as the testis, where a specific 120-kDa testis-specific isoform is expressed, is unknown. To study this, we examined the fertility and testicular histology of gene-targeted hormone-sensitive lipase-deficient mice. Homozygous hormone-sensitive lipase-deficient male mice are infertile and have decreased testis weights; female homozygotes are fertile. Testicular abnormalities, detected at the light and electron microscopic levels, included the presence of multinucleated round and elongating spermatids, vacuolization of the seminiferous epithelium, asynchronization of the spermatogenic cycle, sloughing of postmeiotic germ cells from the seminiferous epithelium into the lumen, and a marked reduction in the numbers of late spermatids. Extensive nuclear head deformation was noted in late spermatids as well as the sharing of a common acrosome in multinucleated cells. In some multinucleated cells, nuclei were separated from their acrosomes, with the acrosomes remaining attached to areas of ectoplasmic specializations, suggesting defects in intercellular cytoplasmic bridge integrity. Although the lumen of the epididymis was essentially devoid of spermatozoa and filled instead with spherical degenerating cells, the epididymal epithelial cells appeared normal. The few late spermatids present in the epididymis were abnormal. There was no morphological evidence, as judged by the absence of lipid droplets of triacylglycerol or cholesteryl ester accumulation in the testis. Together, the data suggest that hormone-sensitive lipase deficiency results in abnormalities in spermiogenesis that are incompatible with normal fertility. We speculate that a metabolite downstream from the hormone-sensitive lipase reaction may be essential for membrane stabilization and integrity in the seminiferous epithelium and, in particular, may play an important role in the maintenance of intercellular cytoplasmic bridges between postmeiotic germ cells.

Animals↗
PubMed1987

Effects of feeding monensin to lactating goats: acetyl coenzyme A carboxylase, hormone-sensitive lipase, plasma glucose, and circulating hormones.

These trials explored metabolic events associated with monensin-induced changes in milk composition. In trial 1, diets containing 0 or 33 ppm monensin sodium were fed ad libitum to separate groups of 7 mature lactating goats. In trial 2, diets containing 0 or 18 ppm monensin sodium were fed ad libitum to two groups with 5 mature (greater than 2 yr) and seven young (less than 2 yr) lactating does in each group. Blood was sampled at 1200 h and at 3 min after morning milking in both trials. Diets containing 33 ppm monensin increased serum growth hormone and plasma glucagon. Monensin (33 ppm) increased growth hormone from 13 to 60 ng/ml in samples taken 3 min after milking. Monensin (33 ppm) decreased insulin in these postmilking samples from 432 to 317 pg/ml but increased midday insulin in the samples taken between milkings from 279 to 349 pg/ml. Monensin did not affect plasma glucose or serum prolactin concentrations. Monensin fed at 18 ppm did not affect growth hormone, glucagon, adipose acetyl CoA carboxylase activity, hormone-sensitive lipase, or glucose concentrations. Young animals had higher growth hormone, glucose, and glucagon than mature does. The results indicate that effects of milk production intensity can be more important than monensin treatment on milk composition and circulating hormone concentrations.

Acetyl-CoA Carboxylase↗
PubMed1988

Hormone-sensitive lipase is involved in the hydrolysis of lipoidal derivatives of estrogens and other steroid hormones.

Long-chain fatty acid esters of 17 beta-estradiol and other steroid hormones, which are formed in hormone-sensitive tissues, can be regenerated to the free hormone by the action of an esterase present in the cytosol. This esterase has now been examined in bovine placenta cotyledons. Activity towards steroid fatty acid esters was accompanied by activity towards a diacylglycerol analogue and cholesteryl oleate. During purification procedures, the ratio of activities towards the diacylglycerol analogue and estradiol 17 beta-oleate remained approximately constant. Activity towards these two substrates was inhibited by increasing concentrations of HgCl2 and phenylmethanesulfonyl fluoride in a parallel manner. Upon treatment with [3H]diisopropyl fluorophosphate, a major labelled species of Mr approx. 84,000 was formed. Activation by ATP and the catalytic subunit of cAMP-dependent protein kinase occurred. These properties were very similar to those of the hormone-sensitive lipase of bovine adipose tissue previously reported and run in parallel in this study. A highly purified preparation of this latter enzyme was found to hydrolyse steroid fatty acid esters and relative activities towards such substrates, diacylglycerol analogue and cholesteryl oleate, were similar to the placenta esterase. When the two esterases were phosphorylated with [gamma-32P]ATP, a labelled species of Mr 84,000 was isolated in both cases by use of an antibody raised against purified hormone-sensitive lipase of bovine adipose tissue. It is concluded that hormone-sensitive lipase is very likely the enzyme responsible for hydrolysis of steroid fatty acid esters in bovine placenta and possibly steroid hormone target tissues in general.

Androgens↗
PubMed2000

Molecular mechanisms regulating hormone-sensitive lipase and lipolysis.

Hormone-sensitive lipase, the rate-limiting enzyme of intracellular TG hydrolysis, is a major determinant of fatty acid mobilization in adipose tissue as well as other tissues. It plays a pivotal role in lipid metabolism, overall energy homeostasis, and, presumably, cellular events involving fatty acid signaling. Detailed knowledge about its structure and regulation may provide information regarding the pathogenesis of such human diseases as obesity and diabetes and may generate concepts for new treatments of these diseases. The current review summarizes the recent advances with regard to hormone-sensitive lipase structure and molecular mechanisms involved in regulating its activity and lipolysis in general. A summary of the current knowledge regarding regulation of expression, potential involvement in lipid disorders, and role in tissues other than adipose tissue is also provided.

Adipose Tissue↗
PubMed1991

Developmental regulation of hormone-sensitive lipase mRNA in the rat: changes in steroidogenic tissues.

The hydrolysis of triglycerides and cholesteryl esters stored within cells is mediated by the enzyme, hormone-sensitive lipase. In adipose tissue and heart, hormone-sensitive lipase primarily hydrolyzes stored triglycerides to free fatty acids, while in steroidogenic tissues, it principally converts cholesteryl esters to free cholesterol for steroid hormone production. To determine whether hormone-sensitive lipase is under tissue-specific, developmental regulation, the steady state levels of hormone-sensitive lipase mRNA were determined in normal rats from late fetal life through 2 years of age. Hormone-sensitive lipase mRNA levels did not appear to vary in adipose tissue from epididymal fat pads obtained from animals between 3 weeks and 2 years of age. In heart, hormone-sensitive lipase mRNA levels were lowest in the fetus increased rapidly within the first day postnatally, and then gradually increased to stable adult levels by 2 months that were 3-fold higher than observed in fetal rats. Steady state mRNA levels of hormone-sensitive lipase in the adrenals were lowest in fetal rats, increased 4-fold during the first day and peaked at levels that were 9-fold higher by the end of the first week. Thereafter, levels fell and remained 3- to 4-fold higher than at birth throughout adult life. Hormone-sensitive lipase mRNA was undetectable in testes before 4 weeks of age and increased 25-fold to stable adult levels between 4 and 12 weeks. Thus, hormone-sensitive lipase is differentially expressed and regulated in a tissue-specific fashion during development and aging.

Actins↗
PubMed1995

Expression of hormone-sensitive lipase in the human colon adenocarcinoma cell line HT29.

Hormone-sensitive lipase expression was studied in the human colon adenocarcinoma cell line, HT29. Diacylglycerol lipase and cholesterol esterase [corrected] activities in HT29 cells were inhibited by known inhibitors of hormone-sensitive lipase (diethyl-p-nitrophenyl phosphate, NaF and HgCl2) to the same extent as in human adipocytes. A polyclonal antiserum directed against rat hormone-sensitive lipase inhibited 89% of HT29 cell lipase activity. HT29 hormone-sensitive lipase was the same size as the adipocyte enzyme as was its mRNA. Complete homology between mRNA sequences in HT29 and adipocyte was demonstrated using ribonuclease protection assay. These data are consistent with the expression of a protein closely related, if not identical, to the enzyme expressed in human adipose tissue. HT29 is the first human cell line where hormone-sensitive lipase expression has been shown.

Adenocarcinoma↗
PubMed1989

Insulin-induced dephosphorylation of hormone-sensitive lipase. Correlation with lipolysis and cAMP-dependent protein kinase activity.

The effect of insulin on the state of phosphorylation of hormone-sensitive lipase, cellular cAMP-dependent protein kinase activity and lipolysis was investigated in isolated adipocytes. Increased phosphorylation of hormone-sensitive lipase in response to isoproterenol stimulation was closely paralleled by increased lipolysis. Maximal phosphorylation and lipolysis was obtained when the cAMP-dependent protein kinase activity ratio was greater than or equal to 0.1, and this corresponded to a 50% increase in the state of phosphorylation of hormone-sensitive lipase. Insulin (1 nM) reduced cAMP-dependent protein kinase activity and also reduced lipolysis with both cAMP-dependent and cAMP-independent antilipolytic effects up to an activity ratio of approximately 0.4, above which the antilipolytic effect was lost. Insulin caused a decrease in the state of phosphorylation of hormone-sensitive lipase at all levels of cAMP-dependent protein kinase activity. Under basal conditions, with cAMP-dependent protein kinase activity at a minimum, this reflected a dephosphorylation of the basal phosphorylation site of hormone-sensitive lipase in a manner not mediated by cAMP. When the cAMP-dependent protein kinase was stimulated to phosphorylate the regulatory phosphorylation site of hormone-sensitive lipase, the insulin-induced dephosphorylation occurred both at the basal and regulatory sites. At low levels of cAMP-dependent protein kinase activity ratios (0.05-0.1), dephosphorylation of the regulatory site correlated with reduced cAMP-dependent protein kinase activity, but not at higher activity ratios (greater than 0.1). Stimulation of cells with isoproterenol produced a transient (1-5 min) peak of cAMP-dependent protein kinase activity and of phosphorylation of hormone-sensitive lipase. The state of phosphorylation also showed a transient peak when the protein kinase was maximally and constantly activated. In the presence of raised levels of cellular cAMP, insulin (1 nM) caused a rapid (t1/2 approximately 1 min) dephosphorylation of hormone-sensitive lipase. In unstimulated cells the reduction in phosphorylation caused by insulin was distinctly slower (t1/2 approximately 5 min). These findings are interpreted to suggest that insulin affects the state of phosphorylation of hormone-sensitive lipase and lipolysis through a cAMP-dependent pathway, involving reduction of cAMP, and through a cAMP-independent pathway, involving activation of a protein phosphatase activity that dephosphorylates both the regulatory and basal phosphorylation sites of hormone-sensitive lipase.

Adipose Tissue↗
PubMed2003

Letting lipids go: hormone-sensitive lipase.

PURPOSE OF REVIEW: Despite their pathophysiological importance, the molecular mechanisms and enzymatic components of lipid mobilization from intracellular storage compartments are insufficiently understood. The aim of this review is to evaluate the role of hormone-sensitive lipase in this process. RECENT FINDINGS: Hormone-sensitive lipase exhibits a broad specificity for lipid substrates such as triglycerides, diglycerides, cholesteryl esters, and retinyl esters and the enzyme is in a wide variety of tissues. The high enzyme activity in adipose tissue was considered rate-limiting in the degradation of stored triglycerides. This view of a single enzyme controlling the catabolism of stored fat was challenged by recent findings that in hormone-sensitive lipase deficient mice adipose tissue triglycerides were still hydrolyzed and that these animals were leaner than normal mice. These results indicated that in adipose tissue hormone-sensitive lipase cooperates with other yet unidentified lipases to control the mobilization of fatty acids from cellular depots and that this process is coordinately regulated with lipid synthesis. Induced mutant mouse lines that overexpress or lack hormone-sensitive lipase also provided evidence that hormone-sensitive lipase-mediated cholesteryl ester hydrolysis is involved in steroid-hormone production in adrenals and affects testis function. Finally, hormone-sensitive lipase deficiency in mice results in a lipoprotein profile characterized by low triglyceride and VLDL levels and increased HDL cholesterol concentrations. SUMMARY: The 'anti-atherosclerotic' plasma lipoprotein profile and the fact that hormone-sensitive lipase deficient animals become lean identifies the inhibition of hormone-sensitive lipase as a potential target for the treatment of lipid disorders and obesity.

Adipose Tissue↗
PubMed2000

Changes in adipose tissue hormone-sensitive lipase activity and cAMP during ethanol withdrawal.

The time course of the effects of ethanol withdrawal on brown and white adipose tissue hormone-sensitive lipase, cAMP production, and phosphodiesterase have been investigated after chronic drinking or liquid diet schedules. Chronic drinking significantly reduced brown adipose tissue hormone-sensitive lipase activity and cAMP levels from control. During withdrawal, there was a rebound increase to 200% control, peaking 9 h into withdrawal. White adipose tissue hormone-sensitive lipase activity and cAMP accumulation were significantly raised by both treatment schedules. Ethanol liquid diet produced a significant fall in adipose tissue hormone-sensitive lipase activity and cAMP accumulation. In brown fat, there was a rebound increase in hormone-sensitive lipase activity and cAMP; in white fat, no rebound was observed. In brown fat, the reductions in hormone-sensitive lipase activity and cAMP accumulation after chronic drinking coincided with an increase in phosphodiesterase activity. In white fat, the rise in cAMP and hormone-sensitive lipase activation coincided with a decrease in phosphodiesterase activity. We conclude that the effects of chronic ethanol on hormone-sensitive lipase activity are cAMP-dependent and mediated via alterations in phosphodiesterase activity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1981

Human mutation affecting hormone-sensitive adenylate cyclase.

Hormone-sensitive adenylate cyclase contains a recently discovered protein component that is required for stimulation of cyclic AMP synthesis by hormones and guanine nucleotides. We measured this protein in erythrocyte membranes of ten patients with pseudohypoparathyroidism (PHP), using assays of its biochemical activity and of its susceptibility to radiolabeling in the presence of 32P-NAD and cholera toxin. By both assays, the protein was reduced by 50% in erythrocytes of 4 PHP patients, as compared with normal and hypoparathyroid subjects. These 4 subjects, in contrast to the 6 PHP patients (5 in one family) whose erythrocytes contained apparently normal amounts of the cyclase component, exhibited the full spectrum of skeletal abnormalities found in PHP. We conclude that partial deficiency of the guanine nucleotide regulatory protein is a biochemical marker for a subset of PHP patients. If present in other tissues, this deficiency could explain the resistance of target organs in PHP to parathormone and other hormones that work via cyclic AMP.

Adenylyl Cyclases↗
PubMed1977

Role of phosphoprotein phosphatases in reversible deactivation of chicken adipose tissue hormone-sensitive lipase.

The reversible deactivation of chicken adipose tissue hormone-sensitive lipase alpha(previously activated with Mg2+ ATP and adenosine 3':5'-monophosphate) required Mg2+ and was inhibited by phosphate. These results are consistent with the assumption that deactivation of the protein kinase-activated enzyme is catalyzed by a lipase phosphatase. Cholesterol ester is catalyzed by a lipase phosphatase. Cholesterol ester hydrolase similarly was activated and reversibly deactivated. The activity of endogenous lipase phosphatase in pH 5.2 precipitate fractions was reduced, and in some cases eliminated, by incubation at 50 degrees for 20 min in buffer containing 20% glycerol. Heating at 50 degrees greatly increased the apparent percentage activation of triglyceride and cholesterol ester hydrolases but this was due to a selective decrease in basal (nonactivated) hydrolase activities. Essentially all endogenous lipase phosphatase could be removed by treatment of the pH 5.2 precipitate fraction with ATP-Sepharose affinity gel. The addition of a partially purified preparation of rat liver phosphorylase phosphatase deactivated triglyceride and cholesterol ester hydrolases. The deactivation process was concentration, 5 mM) and was inhibited by 5 mM phosphate and by phosphorylase alpha. Reversible deactivation of hormone-sensitive lipase alpha was also observed with crude prepa- and by phosphorylase alpha. Reversible deactivation of hormone-sensitive lipas alpha was also observed with crude preparations of phosphoprotein phosphatases from rat and turkey hearts, and from rat epididymal fat pads. Thus, hormone-sensitive lipase is deactivated by a variety of phosphoprotein phosphatases from different tissues and different species, implying a low degree of specificity for the deactivating system.

Adenosine Triphosphate↗
PubMed1991

Calcium regulation of hormonal-sensitive phospholipase C.

Numerous hormones or neurotransmitters regulate the activity of their target cell via the activation of a specific phospholipase C. Two intracellular second messengers are generated, diacylglycerol which activates protein kinase C and inositol (1,4,5)P3 which mobilizes calcium from intracellular stores. Both these molecules trigger within the cell biological effects associated with the hormone considered. In these transduction mechanisms, calcium mobilization is a consequence of primary activation of phospholipase C. However calcium is also able to regulate phospholipase C activity since, in many cellular systems, calcium by itself stimulates phosphoinositol lipid metabolism. Such results imply that all molecules which modify the intracellular calcium concentration may be considered as potent regulators of phospholipase C activity. Data obtained on different cell systems favours this hypothesis: Activators of calcium influx stimulate intracellular inositol phosphate accumulation and molecules which reduce intracellular calcium concentration reduce inositol phosphate production. Thus calcium may play an important role in the regulation of hormonal sensitive phospholipase C activities.

Animals↗
PubMed2006

Basic research for hormone-sensitivity of breast cancer.

Hormonal therapy is a rapidly progressing molecular-targeted therapy for breast cancer, using drugs such as LH-RH agonists, SERMs and aromatase inhibitors. Basic research for estrogen signaling and hormone sensitivity in breast cancer cells strongly contributes to the progression of clinical treatment of breast cancer. However, further problems remain unresolved, for example the accurate prediction of individual response to each hormonal therapy. Moreover, novel combinations with other molecular-targeted therapies might be advance the effectiveness of hormonal therapies. To address these issues, we are developing several new tools such as focused microarray and a GFP-reporter cell system. We first identified estrogen-responsive genes by comprehensive expression profiling of estrogen receptor (ER)-positive breast cancer cells, and produced a custom-made estrogen-responsive microarray of a narrowed-down subset. Using this microarray, we studied several basic issues regarding estrogen signaling and expression analysis of estrogen-responsive genes in breast cancer tissues. Furthermore, expression of several candidate genes selected from the contents of the customarray was also analyzed by real-time RT-PCR and by immunohistochemical techniques, to find new predictive factors for responsiveness to hormone therapy for primary breast cancer patients. We found that the expression of several genes such as HDAC6 significantly correlated with disease-free and overall survival of ER-positive patients. Furthermore, we are developing a new tool for analyzing the estrogen-related microenvironment on individual breast cancer patients using ERE-GFP-indicator cells. This system enables visualization of tumor-stroma interactions and the effects of aromatase inhibitors in an individual breast cancer sample. We believe that these approaches could provide not only new clues to elucidate the estrogen-dependent mechanisms of cancer, but also clinical benefits to patients by predicting individual response to hormonal therapy.

Adult↗
PubMed1974

The mechanism of activation of hormone-sensitive lipase in human adipose tissue.

A partially purified hormone-sensitive triglyceride lipase of human adipose tissue was found to be activated twofold by the addition of cyclic 3',5'-AMP, ATP, and magnesium ions. Lipase activities against diolein and monoolein were not affected. Addition of protein kinase inhibitor at zero time completely inhibited activation, and this inhibition was prevented by prior addition of an excess of exogenous protein kinase (from rabbit skeletal muscle). Addition of protein kinase inhibitor during the activation step blocked the activation process without a time lag, suggesting that protein kinase operates directly on hormone-sensitive lipase. Further purification yielded a fraction free of protein kinase, and lipase activation in this fraction depended absolutely on addition of exogenous kinase. Incubation of human fat with epinephrine or isoproterenol stimulated lipolysis and caused conversion of nonactivated hormone-sensitive lipase to its activated form, as indicated by a decrease in the activation subsequently obtainable in fractions prepared from such hormone-treated tissues. These findings strongly suggest that the stimulation of lipolysis by hormonal treatment is the consequence of the activation of hormone-sensitive triglyceride lipase by cyclic 3',5'-AMP-dependent protein kinase.

Adenosine Triphosphate↗
PubMed1995

The hormone-sensitive lipase (LIPE) gene located on chromosome 19q13.1-->13.2 is not duplicated on 19p13.3.

The existence of a DNA polymorphism at the hormone-sensitive lipase locus could be of great interest for genetic analysis of obesity and related disorders since hormone-sensitive lipase is the rate-limiting enzyme of adipose tissue lipolysis and therefore plays a key role in energy metabolism. The polymorphic dinucleotide repeat D19S120 was identified within a human genomic clone selected with a rat hormone-sensitive lipase cDNA. This marker was subsequently localized to the short arm of chromosome 19 (p13.3) whereas human hormone-sensitive lipase (LIPE) had been mapped to the long arm of chromosome 19 (q13.1-->13.2). A duplication of the hormone-sensitive lipase gene or the presence of a pseudogene could explain the discrepancy. Cosmids from the two regions were analyzed in Southern blot experiments. A human adipose tissue hormone-sensitive lipase full-length cDNA probe hybridized only to cosmids from the 19q13.1-->13.2 region whereas the D19S120 amplicon probe hybridized only to cosmids from the p13.3 region. These data show that the occurrence of gene duplication or the presence of a pseudogene on the short arm of chromosome 19 is very unlikely and that D19S120 is unrelated to the hormone-sensitive lipase gene.

Adipose Tissue↗
PubMed1993

Chronic exposure of rat fat cells to insulin enhances lipolysis and activation of partially purified hormone-sensitive lipase.

The activity of adipose tissue hormone-sensitive lipase in animals with hyperinsulinemia has been reported to be increased compared with that in control animals. We examined whether this results from a direct effect of insulin on the tissue and whether it is accompanied by alteration in the regulation of lipolysis. When rat epididymal fat pads are incubated in culture medium with bovine serum albumin for 2-4 h with 2 ng/ml or 50 microU/ml of insulin, hormone-sensitive lipase activity in the postmicrosomal supernatant fraction after acid precipitation and activation with ATP-Mg2+ increases significantly compared with preparations from tissues incubated with the vehicle. The specific activities of hormone-sensitive lipase in sonicates of adipocytes after primary culture with insulin at concentrations from 10 to 4000 ng/ml (250 microU to 100 mU/ml) increase in an insulin-dose-related manner. Lipolysis in response to 10(-7) M isoproterenol also increases in an insulin-dose-dependent manner. Enhancement of isoproterenol-mediated lipolysis is not attributable to a difference in the triglyceride content of the cells. Lipolysis caused by the beta-agonist could be completely blocked by the simultaneous presence of insulin in both control and insulin-treated cells reflecting normal responsiveness of both types of cells to the acute effect of insulin. Although an increase in lipolysis is seen with norepinephrine and growth hormone after insulin treatment, other lipolytic agents such as ACTH, thyrotropin, and glucagon evoke similar responses in insulin-treated and control cells. The simultaneous presence of growth hormone and insulin during the 16-h culture results in additive effects on the subsequent response of the cells to 10(-7) M isoproterenol compared with the responses of the cells cultured with each hormone alone. beta-Agonist-mediated cAMP accumulation in the presence of Ro-20.1724, a specific phosphodiesterase inhibitor, is significantly higher in cells cultured in the presence of insulin than in control cells. Forskolin (1-25 microM) increases the lipolytic responses of insulin-treated cells compared with control cells, but the maximal response of the insulin-treated cells to forskolin is lower than that to isoproterenol. We conclude that changes produced by chronic insulin treatment involve more than one site along the lipolytic cascade.

3',5'-Cyclic-AMP Phosphodiesterases↗