Summary
Glucocorticoids stimulate the rate of lipolysis which is reduced in adrenalectomized animals. This hormonal action is antagonized by insulin. The antilipolytic action of insulin appears to be mediated by a reduced intracellular concentration of 3′,5′-AMP. This reduction can partly be attributed to an insulin-induced acceleration of 3′,5′-AMP degradation. — It is shown that the stimulatory influence of glucocorticoids on lipolysis is due to a reduction of 3′,5′-AMP phosphodiesterase (PDE) activity, which is increased by adrenalectomy. PDE activity was also increased in liver, skeletal muscle and kidney of adrenalectomized rats; treatment with a glucoeorticoid prevented this increase.In vitro, PDE purified from beef heart was inhibited by glucocorticoids in high concentrations (Ki=1.1 · 10−3 M for 6 α-methylprednisolone hemisuccinate,K i=1.6 · 10−3 M for prednisolone succinate).In vivo, the glucocorticoid-induced decrease of PDE activity (with retarded onset as shown in liver), may essentially be attributed to a decreased enzyme synthesis. — Studies on the interaction of insulin and glucocorticoids on PDE activity were performed in the liver. In adrenalectomized, alloxan diabetic rats insulin stimulated PDE activity suppressed by treatment with a glucoeorticoid, unsuppressed PDE activity was not increased by insulin. In contrast, the action of glucocorticoids on PDE activity was independent of the presence or the effectiveness of insulin.
Résumé
Les glucocorticoïdes stimulent la lipolyse qui est réduite chez les animaux surrénalectomisés. Cette action hormonale est contrecarrée par l'insuline. L'action antilipolytique de l'insuline semble être due à une réduction de la concentration intracellulaire de 3′5′-AMP. Cette réduction peut être attribuée en partie à une accélération due à l'insuline de la dégradation du 3′5′-AMP. On a montré que l'influence stimulatrice des glucocorticoïdes sur la lipolyse est due à une réduction de l'activité de la 3′5′-AMP-phosphodiesterase (PDE), qui est accrue par la surrénalectomie. L'activité de la phosphodiesterase est également augmentée dans le foie, le muscle strié et les reins des rats surrénalectomisés, le traitement par un glucocorticoïde prévient cette augmentation.In vitro, la phosphodiesterase purifiée du coeur de boeuf est inhibée par les glucocorticoïdes à fortes concentrations (K i=1.1 · 10−3 M pour l'hémisuccinate de 6 α-méthylprednisolone, (K i=1.6 · 10−3 M pour le succinate de prednisolone).In vivo, la diminution provoquée par les glucocorticoïdes de l'activité de la phosphodiesterase qui se produit au bout de quelque temps, comme on l'a montré dans le foie, peut essentiellement être attribuée à une synthèse diminuée de l'enzyme. Des études sur l'interaction de l'insuline et des glucocorticoïdes sur l'activité de la phosphodiesterase ont été effectuées sur le foie. Chez les rats surrénalectomisés, rendus diabétiques par l'alloxane, l'insuline stimule l'activité de la phosphodiesterase qui a été supprimée par un traitement avec un glucocorticoïde, l'activité de la phosphodiesterase qui n'a pas été supprimée n'est pas augmentée par l'insuline. Par contre, l'action des glucocorticoïdes sur l'activité de la phosphodiesterase est indépendante de l'action de l'insuline.
Zusammenfassung
Die Lipolyse, die bei adrenalektomierten Tieren vermindert ist, wird durch Glucocorticoide verstärkt. Die gegenüber Glucocorticoiden antagonistische Wirkung von Insulin, das die Lipolyse vermindert, kann durch eine Abnahme der intracellulären 3′,5′-AMP-Konzentration erklärt werden. Diese ist teilweise auf einen beschleunigten Abbau des Nucleotids zurückzuführen. — Die Lipolysesteigerung durch Glucocorticoide ist durch eine Verminderung der 3′,5′-AMP-Phosphodiesterase (PDE)-Aktivität bedingt, die bei adrenalektomierten Ratten erhöht ist. Die PDE-Aktivität adrenalektomierter Tiere ist auch in Leber, Skeletmuskulatur und Niere erhöht, die Gabe eines Glucocorticoids verhindert diesen Anstieg. Glucocorticoide hemmen aus Rinderherz isolierte PDEin vitro, jedoch sind hohe Steroidkonzentrationen erforderlich (K i=1.1 · 10−3 M für 6 α-Methylprednisolon-Hemisuceinat, (K i=1,6 · 10−3 M für Prednisolon-Succinat). Die einige Stunden nach Gabe eines Glucocorticoids einsetzende Abnahme der PDE-Aktivität kann im wesentlichen auf eine verminderte Enzymsynthese zurückgeführt werden. — Insulin steigert bei adrenalektomierten, alloxandiabetischen Ratten die PDE-Aktivität in der Leber nur, wenn die Tiere mit einem Glucocorticoid behandelt sind, nicht jedoch die erhöhte PDE-Aktivität bei Fehlen von Glucocorticoiden. Der Einfluß von Glucocorticoiden auf die PDE-Aktivität ist dagegen nicht an die Wirkung von Insulin gebunden.
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Abbreviations
- G 6 P:
-
Glucose-6-phosphate
- FFA:
-
non-esterified, free fatty acids
- 3′,5′-AMP:
-
cyclic adenosine-3′,5′-monophosphate
- PDE:
-
3′,5′-AMP phosphodiesterase
References
Adam, H.: In H.U. Bergmeyer: Methoden der enzymatischen Analyse. Weinheim: Verlag Chemie 1962.
Bartelheimer, H.K., W. Losert, G. Senft, andR. Sitt: Störungen des Kohlenhydratstoffwechsels im Kaliummangel. Naunyn-Schmiedeberg's Arch. Pharmak. exp. Path.258, 391–408 (1967).
Bieck, P., K. Stock, andB. Westermann: Über die Bedeutung des Serotonins im Fettgewebe, Naunyn-Schmiedebergs Arch. Pharmak. exp. Path.256, 218–236 (1967).
Butcher, R.W., andE.W. Sutherland: Adenosine 3′,5′-phosphate in biological materials. I. Purification and properties of cyclic 3′,5′-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3′,5′-phosphate in human urine. J. biol. Chem.237, 1244–1250 (1962).
Butcher, R.W., andE.W. Sutherland: The effects of the catecholamines, adrenergic blocking agents, prostaglandin E1, and insulin on cyclic AMP levels in the rat epididymal fat pad in vitro. Ann. N.Y. Acad. Sci.139, 849–859 (1967).
Butcher, R.W., J.G.T. Sneyd, C.R. Park, andE. W. Sutherland jr.: Effect of insulin on adenosine 3′,5′-monophosphate in the rat epididymal fat pad. J. biol. Chem.241, 1651–1653 (1966).
Daligcon, B.C., andJ. Oyama: In vivo effect of glucose, corticosterone and insulin on rat liver glycogen synthetase. Fed. Proc.26, 484 (1967).
De Wulf, H., andH.G. Hers: The stimulation of glycogen synthesis and of glycogen synthetase in the liver by the administration of glucose. Europ. J. Biochem.2, 50–56 (1967).
Fain, J.N.: Effect of puromycin on incubated adipose tissue and its response to dexamethasone, insulin, and epinephrine. Biochim. biophys. Acta84, 639–642 (1964).
—,R.O. Scow, andS.S. Chernick: Effects of glucocorticoids on metabolism of adipose tissue in vitro. J. biol. Chem,238, 54–58 (1963).
—,V.P. Kovacev, andR.O. Scow: Antilipolytic effect of insulin in isolated fat cells of the rat. Endocrinology78, 773–778 (1966).
Froesch, R.E., J. Ashmore, andA.E. Renold: Comparison of renal and hepatic effects of fasting, cortisone adminstration and glucose infusion in normal and adrenalectomized rats. Endocrinology62, 614–620 (1958).
Glenn, E.M.: Steroids, nonsteroids, intermediary metabolism, inflammation and their probable interrelationships, in: Hormonal steroids, ed. by I. Martini and A. Pecile, p. 319. New York, London: Academic Press 1964.
Goldberg, I.H., M. Rabinowitz, andE. Reich: Basis of actinomycon action. I. DNA binding and inhibition of RNA-polymerase synthetic reactions by actinomycin. Proc. nat. Acad. Sci. (Wash.)48, 2094–2101 (1962).
Goodman, H.M., andE. Knobil: Some endocrine factors in regulation of fatty acid mobilization during fasting. Amer. J. Physiol.201, 1–3 (1961).
Gordon, R.S., jr.: Unesterified fatty acid in human blood plasma, II. The transport function of unesterified fatty acid. J. clin. Invest.36, 810–815 (1957).
Hilz, H., W. Tarnowski, andP. Arend: Glucose polymerisation and cortisol. Biochem. biophys. Res. Comm.10, 492–497 (1963).
Huijing, F., andJ. Larner: On the mechanism of action of adenosine 3′,5′-cyclophosphate. Proc. nat. Acad. Sci. (Wash.)56, 647–653 (1966).
Jeanrenaud, B., andA.E. Renold: Studies on rat adipose tissue in vitro. VII. Effects of adrenal cortical hormones. J. biol. Chem.235, 2217–2223 (1960).
Jungas, R.L.: Role of cyclic 3′,5′-AMP in the response of adipose tissue to insulin. Proc. nat. Acad. Sci. (Wash.)56, 757–763 (1966).
—, andE.G. Ball: Studies on the metabolism of adipose tissue. XII. The effects of insulin and epinephrine on free fatty acid and glycerol production in the presence and absence of glucose. Biochemistry2, 383–388 (1963).
Kovacev, V.P., andR.O. Scow: Effect of hormones on fatty acid release by rat adipose tissue in vivo. Amer. J. Physiol.210, 1199–1208 (1966).
Kreutner, W., andN.D. Goldberg: Dependence on insulin of the apparent hydrocortisone activation of hepatic glycogen synthetase. Proc. nat. Acad. Sci. (Wash.)58, 1515–1519 (1967).
Lardy, H.A.: Gluconeogenesis: Pathways and hormonalregulation. Harvey Lect.60, 261–278 (1965).
Leites, S.M., andN.K. Davtyan: Permissive role of glucocorticoids in mobilization of fat from adipose tissue. Fed. Proc.25, T 67 (1966).
Maickel, R.P., andB.B. Brodie: Interaction of drugs with the pituitary-adrenocortical system in the production of the fatty liver. Ann. N.Y. Acad. Sci.104, 1059–1064 (1963).
Malaisse, W., F. Malaisse-Lagae, E.F. McCraw, andP.H. Wright: Insulin secretion in vitro by pancreatic tissue from normal, adrenalectomized, and cortisol treated rats. Proc. Soc. exp. Biol. (N.Y.)124, 924–928 (1967).
Pätau, K.: Zur statistischen Beurteilung von Messungsreihen. (Eine t-Tafel). Biol. Zbl.63, 152–168 (1943).
Reshef, L., andB. Shapiro: Effect of epinephrine, cortisone and growth hormone on release of unesterifled fatty acids by adipose tissue in vitro. Metabolism9, 551–555 (1961).
Rizack, M.A.: Activation of an epinephrine-sensitive lipolytic activity from adipose tissue by adenosine 3′,5′-phosphate, J. biol. Chem239, 392–395 (1964).
Rodbell, M., andA.B. Jones: Metabolism of isolated fat cells. III. The similar inhibitory action of phospholipase C (clostridium perfringens α toxin) and of insulin on lipolysis stimulated by lipolytic hormones and theophylline. J. biol. Chem.241, 140–142 (1966).
Schultz, G., G. Senft, W. Losert, andR. Sett: Biochemische Grundlagen der Diazoxid-Hyperglykämie. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path.253, 372–387 (1966).
Senft, G., G. Schultz, K. Munske, andM. Hoffmann: Influence of insulin on cyclic 3′,5′-AMP phosphodiesterase activity in liver, skeletal muscle, adipose tissue, and kidney. Diabetologia4, 322–329 (1968).
Shafrir, E., andD. Steinberg: The essential role of the adrenal cortex in the response of plasma free fatty acids, cholesterol, and phospholipids to epinephrine injection. J. clin. Invest.39, 310–319 (1960).
—,K.E. Sussman, andD. Steinberg: Role of the pituitary and the adrenal in the mobilization of free fatty acids and lipoproteins. J. Lipid Res.1, 459–465 (1960).
Sie, H.-G., A. Hablanian, andW.H. Fishman: Divergent effects of actinomycin D on cortisol and on glucose stimulation of glycogenesis in mouse liver. Biochem. J.102, 103–109 (1967).
Steiner, D.F., andJ. King: Induced synthesis of hepatic uridine diphosphate glucose-glycogen glucosyltransferase after administration of insulin to alloxan-diabetic rats. J. biol. Chem.239, 1292–1298 (1964).
—,L. Younger, andJ. King: Purification and properties of uridine diphosphate glucose-glycogen glucosyltransferase from rat liver. Biochemistry4, 740–751 (1965).
—,V. Rauda, andR.H. Williams: Effects of insulin, glucagon, and glucocorticoids upon hepatic glycogen synthesis from uridine diphosphate glucose. J. biol. Chem.236, 299–304 (1961).
Weber, G., R.L. Singhal, andS.K. Srivastava: Action of glucocorticoid as inducer and insulin as suppressor of biosynthesis of hepatic gluconeogenic enzymes. In: Advances in Enzyme Regulation, Vol. 3, p. 369, ed. by G. Weber. Oxford: Pergamon Press 1965.
— —,N.B. Stamm, E.A. Fisher, andM.A. Mentendiek: Regulation of enzymes involved in gluconeogenesis. In: Advances in Enzyme Regulation, Vol. 2, p. 1, ed. by G. Weber. Oxford: Pergamon Press 1964.
Weinges, K.F., andG. Loffler: Der Einfluß von Cortisol auf den Insulineffekt am Fettgewebe in vitro. Klin. Wschr.42, 502–503 (1964).
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This study was supported by the Deutsche Forschungsgemeinschaft.
Deceased October 31, 1967.
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Senft, G., Schultz, G., Munske, K. et al. Effects of glucocorticoids and insulin on 3′,5′-AMP phosphodiesterase activity in adrenalectomized rats. Diabetologia 4, 330–335 (1968). https://doi.org/10.1007/BF01211767
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DOI: https://doi.org/10.1007/BF01211767