Hemmung der Lipolyse im Fettgewebe durch Methylisoxazolcarbonsäuren

Inhibition of lipolysis in adipose tissue by methylisoxazolcarboxylic acids

Summary

5-Methylisoxazole-3-carboxylic acid (5-MICA) and 3-methylisoxazole-5-carboxylic acid (3-MICA) are strong inhibitors of fatty acid mobilization, 5-MICA being somewhat more potent than 3-MICA. Low doses of 5-MICA (20 μg/kg s.c.) depress plasma levels of unesterified fatty acids (UFA) in rats and small concentrations (10−7 m) reduce lipolysis in adipose tissue of fasting rats in vitro. 5-MICA acts on triglyceride hydrolysis, because it affects the release of UFA and glycerol to an equal extent. The antilipolytic effect is not associated with an increased reesterification, as the 14C-incorporation from glucose-U-14C into triglyceride-glycerol is reduced. Other pathways of glucose metabolism, however, such as oxidation to CO2 and fatty acid synthesis are stimulated. The incorporation of palmitate-1-14C into esterified fatty acids of isolated adipose tissue is also enhanced. Concentrations of 8·10−7 m 5-MICA totally prevent the lipolytic effects of caffeine and theophylline. On the other hand the lipolytic action of norepinephrine is only depressed to 70% by 8·10−5 m 5-MICA. The stronger inhibitory effect of 5-MICA on the lipolytic response evoked by a blockade of the phosphodiesterase suggests, that the antilipolytic action of 5-MICA could depend on an activation of the 3′,5′-AMP-phosphodiesterase.

Zusammenfassung

5-Methylisoxazol-3-carbonsäure (5-MICS) und 3-Methyl-isoxazol-5-carbonsäure (3-MICS) lösen eine starke Hemmung der Fettsäuremobilisation aus, wobei 5-MICS etwas wirksamer als 3-MICS ist. 5-MICS senkt den Plasmaspiegel der unveresterten Fettsäuren (UFS) in einer Dosis von 20 μg/kg s.c. und vermindert die Hungerlipolyse am Fettgewebe in vitro in einer Konzentration von 10−7 m. 5-MICS wirkt auf die Triglyceridspaltung im Fettgewebe, da nicht nur weniger UFS, sondern auch weniger Glycerin freigesetzt werden. Eine erhöhte Wiederveresterung von Fettsäuren ist nicht beteiligt, da der 14C-Einbau von Glucose-U14-C in das Triglycerid-Glycerin sogar etwas abnimmt. Andere Stoffwechselwege der Glucose, die Oxydation zu CO2 und die Fettsäuresynthese werden dagegen durch 5-MICS gesteigert. Auch der Einbau von Palmitat-1-14C in die Fettsäureester des isolierten Fettgewebes nimmt zu. 5-MICS hebt die Coffein- und Theophyllinlipolyse in vitro schon in Konzentrationen von 8·10−7 m vollständig auf. Die Noradrenalinlipolyse wird jedoch durch 8·10−5 m 5-MICS nur um 70% reduziert. Der stärkere Effekt auf eine Lipolyse, die durch Phosphodiesterasehemmung ausgelöst wird, könnte ein Hinweis dafür sein, daß die antilipolytische Wirkung der 5-MICS auf einer Aktivierung der 3′,5′-AMP-Phosphodiesterase beruht.

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Literatur

  1. Bergström, S., L. A. Carlson, and L. Orö: Effect of prostaglandins on catecholamine induced changes in the free fatty acids of plasma and in blood pressure in the dog. Acta physiol. scand. 60, 170 (1964).

    Google Scholar 

  2. Bizzi, A., S. Garattini, and E. Veneroni: The action of salicylate in reducing plasma free fatty acids and its pharmacological consequences. Brit. J. Pharmacol. 25, 187 (1965).

    Google Scholar 

  3. ——, and S. Garattini: Effect of 3,5-dimethylpyrazole on blood free fatty acids and glucose. Life Sci. 3, 1371 (1964).

    Google Scholar 

  4. Bubenheimer, P., A. Hasselblatt u. U. Schwabe: Hemmung der Ketonämie bei Hunger und Insulinmangel durch 3,5-Dimethylisoxazol. Klin. Wschr. 44, 713 (1966).

    Google Scholar 

  5. Butcher, R. W., R. J. Ho, H. C. Meng, and E. W. Sutherland: Adenosine-3′,5′-monophosphate in biological materials. II: The measurement of cyclic 3′,5′-AMP in tissues and the role of the cyclic nucleotide in the lipolytic response of fat to epinephrine. J. biol. Chem. 240, 4515 (1965).

    Google Scholar 

  6. Carlson, L. A.: Studies on the effect of nicotinic acid on catecholamine stimulated lipolysis in adipose tissue in vitro. Acta med. scand. 173, 719 (1963).

    Google Scholar 

  7. ——, and P. R. Bally: Inhibition of lipid mobilization. Handbook of Physiology, Section 5: Adipose Tissue, p. 557. Baltimore: Williams and Wilkins 1965.

    Google Scholar 

  8. ——, and L. Orö: The effect of nicotinic acid on the plasma free fatty acids. Demonstration of a metabolic type of sympathicolysis. Acta med. scand. 172, 641 (1962).

    Google Scholar 

  9. ——, and J. Östman: Effect of salicylates on plasma-free fatty acid in normal and diabetic subjects. Metabolism 10, 781 (1961).

    Google Scholar 

  10. Cherkes, L. A., and E. L. Rozenfeldt: Effect of nicotinic acid on the blood sugar level and its relationship to adrenalin hyperglycemia. Biokhimiya 6, 58 (1941).

    Google Scholar 

  11. Dole, V. P., and H. Meinertz: Microdetermination of long-chain fatty acids in plasma and tissues. J. biol. Chem. 235, 2595 (1960).

    Google Scholar 

  12. Dulin, W. E., and G. C. Gerritsen: Hypoglycemic activity of 3,5-dimethyl-isoxazole. Proc. Soc. exp. Biol. (N.Y.) 113, 683 (1963).

    Google Scholar 

  13. —— —— Effects of 5-carboxy-3-methylisoxazole on carbohydrate and fat metabolism. Proc. Soc. exp. Biol. (N.Y.) 121, 777 (1966).

    Google Scholar 

  14. ——, and G. C. Gerritsen: Effects of 3,5-dimethylisoxazole (U-21221) on fat metabolism. Proc. Soc. exp. Biol. (N.Y.) 118, 499 (1965).

    Google Scholar 

  15. Folch, J., M. Lees, and G. H. Sloanestanley: A simple method for the isolation and purification of total lipides from animal tissues. J. biol. Chem. 226, 497 (1957).

    Google Scholar 

  16. Froesch, E. R., M. Waldvogel, U. A. Meyer, A. Jacob, and A. Labhart: Effects of 5-methylpyrazole-3-carboxylic acid on adipose tissue. I. Inhibition of lipolysis, effects on glucose, fructose, and glycogen metabolism in vitro and comparison with insulin. Molec. Pharmacol. 3, 429 (1967).

    Google Scholar 

  17. Gerritsen, G. C., and W. E. Dulin: Effect of a new hypoglycemic agent, 3,5-dimethylpyrazole, on carbohydrate and free fatty acid metabolism. Diabetes 14, 507 (1965).

    Google Scholar 

  18. —— —— The effect of 5-methylpyrazole-3-carboxylic acid on carbohydrate and free fatty acid metabolism. J. Pharmacol. exp. Ther. 150, 491 (1965).

    Google Scholar 

  19. Handel, E. van: Suggested modifications of the micro determination of triglycerides. Clin. Chem. 7, 249 (1961).

    Google Scholar 

  20. Hynie, S., G. Krishna, and B. B. Brodie: Theophylline as a tool in studies of the role of cyclic adenosine-3′,5′ monophosphate in hormone-induced lipolysis. J. Pharmacol. exp. Ther. 153, 90 (1966).

    Google Scholar 

  21. Kerpel, S., E. Shafrir, and B. Shapiro: Mechanism of fatty acid assimilation in adipose tissue. Biochim. biophys. Acta (Amst.) 46, 495 (1961).

    Google Scholar 

  22. Krishna, G., B. Weiss, J. I. Davies, and S. Hynie: Mechanism of nicotinic acid inhibition of hormone-induced lipolysis. Fed. Proc. 25, 719 (1966).

    Google Scholar 

  23. Lambert, M., and A. C. Neish: Rapid method for estimation of glycerol in fermentation solutions. Canad. J. Res., Section B 28, 83 (1950).

    Google Scholar 

  24. Lee, H. M., R. M. Ellis, and M. V. Sigal: Some insulin-like effects of nicotinic acid observed in isolated rat epididymal adipose tissue. Biochim. biophys. Acta (Amst.) 49, 408 (1961).

    Google Scholar 

  25. Meltzer, R. I., A. D. Lewis, F. H. McMillan, J. D. Genzer, F. Leonard, and J. A. King: Antituberculur substances. III. Nonpyridinoid heterocyclic hydrazides. J. Amer. pharm. Ass. 42, 594 (1953).

    Google Scholar 

  26. Morgan, G. T., and H. Burgess: Non-aromatic diazonium salts. Part VI. 3,5-Dimethylisoxazole-4-diazonium salts and their azoderivatives. J. chem. Soc. 119, 697 (1921).

    Google Scholar 

  27. Reeves, R. E.: The estimation of primary carbinol groups in carbohydrates. J. Amer. chem. Soc. 63, 1476 (1941).

    Google Scholar 

  28. Rizack, M. A.: Activation of an epinephrine-sensitive lipolytic activity from adipose tissue by adenosine 3′,5′-phosphate. J. biol. Chem. 239, 392 (1964).

    Google Scholar 

  29. Schwabe, U., u. A. Hasselblatt: Abfall von Blutzucker und unveresterten Fettsäuren im Plasma nach Isoxazolderivaten. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 251, 121 (1965).

    Google Scholar 

  30. —— —— Hemmung der Lipolyse im Fettgewebe durch 5-Methylisoxazol-3-carbonsäure. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 255, 76 (1966).

    Google Scholar 

  31. —— —— Vergleich der Wirkung von Insulin und 3,5-Dimethylisoxazol auf den Stoffwechsel der unveresterten Fettsäuren, Glycerin und Glucose. Klin. Wschr. 44, 707 (1966).

    Google Scholar 

  32. Smith, D. L., A. A. Forist, and W. E. Dulin: 5-Methylpyrazole-3-carboxylic acid. The potent hypoglycemic metabolite of 3,5-dimethylpyrazole in rats. J. med. Chem. 8, 350 (1965).

    Google Scholar 

  33. Steinberg, D., M. Vaughan, P. J. Nestel, O. Strand, and S. Bergström: Effects of the prostaglandins on hormone-induced mobilization of free fatty acids. J. clin. Invest. 43, 1533 (1964).

    Google Scholar 

  34. Stock, K., u. E. Westermann: Hemmung der Lipolyse durch α-und β-Sympathicolytica, Nicotinsäure und Prostaglandin E1. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 254, 334 (1966).

    Google Scholar 

  35. Sutherland, E. W., J. Öye, and R. W. Butcher: The action of epinephrine and the role of the adenylcyclase system in hormone action. Recent Progr. Hormone Res. 21, 623 (1965).

    Google Scholar 

  36. Vaughan, M., J. E. Berger, and D. Steinberg: Hormone-sensitive lipase and monoglyceride lipase activities in adipose tissue. J. biol. Chem. 239, 401 (1964).

    Google Scholar 

  37. Wieland, O., u. M. Suyter: Glycerokinase: Isolierung und Eigenschaften des Enzyms. Biochem. Z. 329, 320 (1957).

    Google Scholar 

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Herrn Professor Dr. F. v. Brücke zum 60. Geburtstag gewidmet.

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Schwabe, U., Kerstein, E. & Hasselblatt, A. Hemmung der Lipolyse im Fettgewebe durch Methylisoxazolcarbonsäuren. Naunyn-Schmiedebergs Arch. Pharmak. u. Exp. Path. 260, 1–15 (1968). https://doi.org/10.1007/BF00545003

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Key-Words

  • Isoxazole
  • Fatty Acids
  • Adipose Tissue
  • Lipase
  • Theophylline

Schlüsselwörter

  • Isoxazol
  • Fettsäuren
  • Fettgewebe
  • Lipase
  • Theophyllin