Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Mar 1;88(5):1691–1695. doi: 10.1073/pnas.88.5.1691

Growth hormone inhibits activation of phosphatidylinositol phospholipase C in adipose plasma membranes: evidence for a growth hormone-induced change in G protein function.

P Roupas 1, S Y Chou 1, R J Towns 1, J L Kostyo 1
PMCID: PMC51090  PMID: 1848008

Abstract

Pituitary growth hormone (GH) functions physiologically to oppose the actions of insulin on carbohydrate and lipid metabolism by interfering with metabolic events that occur after insulin binds to its receptor. Which postreceptor effects are involved is presently unknown. Recently, we found that insulin rapidly stimulates a phosphatidylinositol phospholipase C (PI-PLC) in adipose tissue of obese (ob/ob) mice and that this effect of insulin is blocked by treatment of the animals with S-carboxymethylated human GH (RCM-hGH), a derivative having mainly anti-insulin activity. The activation of this PI-PLC by insulin is also inhibited by pertussis toxin. Thus, this study was performed to examine whether the inhibitory effect of GH on the activation of this PI-PLC is exerted at the level of signal transmission by guanine nucleotide binding proteins (G proteins). We found that the nonhydrolyzable GTP analogue, guanosine 5'-[gamma-thio]triphosphate, stimulated basal PI-PLC activity in plasma membranes of adipose tissue of saline-treated ob/ob mice, but it did not stimulate the enzyme in adipose membranes from RCM-hGH-treated mice. Also, RCM-hGH treatment markedly inhibited pertussis toxin-catalyzed ADP ribosylation of G protein alpha subunits in the membranes, suggesting some modification of the G proteins by GH. Immunoblot analysis of adipose membranes from saline- and RCM-hGH-treated mice using antiserum AS/7 (anti-Gi1 alpha and anti-Gi2 alpha) or antiserum EC/2 (anti-Gi3 alpha) showed no difference in the amount of Gi alpha-like protein between the groups. These findings suggest that GH interferes with the ability of a putative Gi-like protein to mediate the activation of PI-PLC in adipose membranes without altering the expression of the G protein.

Full text

PDF
1691

Images in this article

1694Image
on p.1694
1694Image
on p.1694

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adamafio N. A., Kostyo J. L., Cameron C. M., Trimark J. R., Dunbar J. C. Acute effects of S-carboxymethylated human growth hormone on insulin resistance in the obese (ob/ob) mouse. Metabolism. 1988 Sep;37(9):900–905. doi: 10.1016/0026-0495(88)90126-6. [DOI] [PubMed] [Google Scholar]
  2. Augert G., Exton J. H. Insulin and oxytocin effects on phosphoinositide metabolism in adipocytes. J Biol Chem. 1988 Mar 15;263(8):3600–3609. [PubMed] [Google Scholar]
  3. Cameron C. M., Kostyo J. L., Adamafio N. A., Dunbar J. C. Metabolic basis for the diabetogenic action of growth hormone in the obese (ob/ob) mouse. Endocrinology. 1987 Apr;120(4):1568–1575. doi: 10.1210/endo-120-4-1568. [DOI] [PubMed] [Google Scholar]
  4. Cameron C. M., Kostyo J. L. Influence of age on responsiveness to diabetogenic action of growth hormone. Diabetes. 1987 Jan;36(1):88–92. doi: 10.2337/diab.36.1.88. [DOI] [PubMed] [Google Scholar]
  5. Cameron C. M., Kostyo J. L., Rillema J. A., Gennick S. E. Reduced and S-carboxymethylated human growth hormone: a probe for diabetogenic action. Am J Physiol. 1984 Nov;247(5 Pt 1):E639–E644. doi: 10.1152/ajpendo.1984.247.5.E639. [DOI] [PubMed] [Google Scholar]
  6. Chou S. Y., Kostyo J. L., Adamafio N. A. Growth hormone inhibits activation of phosphatidylinositol phospholipase C by insulin in ob/ob mouse adipose tissue. Endocrinology. 1990 Jan;126(1):62–66. doi: 10.1210/endo-126-1-62. [DOI] [PubMed] [Google Scholar]
  7. Davidson M. B. Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev. 1987 May;8(2):115–131. doi: 10.1210/edrv-8-2-115. [DOI] [PubMed] [Google Scholar]
  8. Etindi R., Fain J. N. Insulin does not activate a phosphoinositide-specific phospholipase C in adipocytes. Mol Cell Endocrinol. 1989 Dec;67(2-3):149–153. doi: 10.1016/0303-7207(89)90204-9. [DOI] [PubMed] [Google Scholar]
  9. Farese R. V., Barnes D. E., Davis J. S., Standaert M. L., Pollet R. J. Effects of insulin and protein synthesis inhibitors on phospholipid metabolism, diacylglycerol levels, and pyruvate dehydrogenase activity in BC3H-1 cultured myocytes. J Biol Chem. 1984 Jun 10;259(11):7094–7100. [PubMed] [Google Scholar]
  10. Farese R. V., Cooper D. R. Potential role of phospholipid-signaling systems in insulin action and states of clinical insulin resistance. Diabetes Metab Rev. 1989 Aug;5(5):455–474. doi: 10.1002/dmr.5610050504. [DOI] [PubMed] [Google Scholar]
  11. Farese R. V., Davis J. S., Barnes D. E., Standaert M. L., Babischkin J. S., Hock R., Rosic N. K., Pollet R. J. The de novo phospholipid effect of insulin is associated with increases in diacylglycerol, but not inositol phosphates or cytosolic Ca2+. Biochem J. 1985 Oct 15;231(2):269–278. doi: 10.1042/bj2310269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Farese R. V., Kuo J. Y., Babischkin J. S., Davis J. S. Insulin provokes a transient activation of phospholipase C in the rat epididymal fat pad. J Biol Chem. 1986 Jul 5;261(19):8589–8592. [PubMed] [Google Scholar]
  13. Goldsmith P., Rossiter K., Carter A., Simonds W., Unson C. G., Vinitsky R., Spiegel A. M. Identification of the GTP-binding protein encoded by Gi3 complementary DNA. J Biol Chem. 1988 May 15;263(14):6476–6479. [PubMed] [Google Scholar]
  14. Gottschalk W. K., Jarett L. The insulinomimetic effects of the polar head group of an insulin-sensitive glycophospholipid on pyruvate dehydrogenase in both subcellular and whole cell assays. Arch Biochem Biophys. 1988 Feb 15;261(1):175–185. doi: 10.1016/0003-9861(88)90116-6. [DOI] [PubMed] [Google Scholar]
  15. Greenberg A. S., Taylor S. I., Londos C. Presence of a functional inhibitory GTP-binding regulatory component, Gi, linked to adenylate cyclase in adipocytes of ob/ob mice. J Biol Chem. 1987 Apr 5;262(10):4564–4568. [PubMed] [Google Scholar]
  16. Hesketh J. E., Campbell G. P. Effects of insulin, pertussis toxin and cholera toxin on protein synthesis and diacylglycerol production in 3T3 fibroblasts: evidence for a G-protein mediated activation of phospholipase C in the insulin signal mechanism. Biosci Rep. 1987 Jul;7(7):533–541. doi: 10.1007/BF01119769. [DOI] [PubMed] [Google Scholar]
  17. Houslay M. D., Gawler D. J., Milligan G., Wilson A. Multiple defects occur in the guanine nucleotide regulatory protein system in liver plasma membranes of obese (fa/fa) but not lean (Fa/Fa) Zucker rats: loss of functional Gi and abnormal Gs function. Cell Signal. 1989;1(1):9–22. doi: 10.1016/0898-6568(89)90016-8. [DOI] [PubMed] [Google Scholar]
  18. Koepfer-Hobelsberger B., Wieland O. H. Insulin activates phospholipase C in fat cells: similarity with the activation of pyruvate dehydrogenase. Mol Cell Endocrinol. 1984 Jun;36(1-2):123–129. doi: 10.1016/0303-7207(84)90091-1. [DOI] [PubMed] [Google Scholar]
  19. Larner J., Huang L. C., Schwartz C. F., Oswald A. S., Shen T. Y., Kinter M., Tang G. Z., Zeller K. Rat liver insulin mediator which stimulates pyruvate dehydrogenase phosphate contains galactosamine and D-chiroinositol. Biochem Biophys Res Commun. 1988 Mar 30;151(3):1416–1426. doi: 10.1016/s0006-291x(88)80520-5. [DOI] [PubMed] [Google Scholar]
  20. Low M. G., Saltiel A. R. Structural and functional roles of glycosyl-phosphatidylinositol in membranes. Science. 1988 Jan 15;239(4837):268–275. doi: 10.1126/science.3276003. [DOI] [PubMed] [Google Scholar]
  21. Luttrell L. M., Hewlett E. L., Romero G., Rogol A. D. Pertussis toxin treatment attenuates some effects of insulin in BC3H-1 murine myocytes. J Biol Chem. 1988 May 5;263(13):6134–6141. [PubMed] [Google Scholar]
  22. Lynch C. J., Blackmore P. F., Johnson E. H., Wange R. L., Krone P. K., Exton J. H. Guanine nucleotide binding regulatory proteins and adenylate cyclase in livers of streptozotocin- and BB/Wor-diabetic rats. Immunodetection of Gs and Gi with antisera prepared against synthetic peptides. J Clin Invest. 1989 Jun;83(6):2050–2062. doi: 10.1172/JCI114116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mitchell F. M., Griffiths S. L., Saggerson E. D., Houslay M. D., Knowler J. T., Milligan G. Guanine-nucleotide-binding proteins expressed in rat white adipose tissue. Identification of both mRNAs and proteins corresponding to Gi1, Gi2 and Gi3. Biochem J. 1989 Sep 1;262(2):403–408. doi: 10.1042/bj2620403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peterson G. L. A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem. 1977 Dec;83(2):346–356. doi: 10.1016/0003-2697(77)90043-4. [DOI] [PubMed] [Google Scholar]
  25. Rizza R. A., Mandarino L. J., Gerich J. E. Effects of growth hormone on insulin action in man. Mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization. Diabetes. 1982 Aug;31(8 Pt 1):663–669. doi: 10.2337/diab.31.8.663. [DOI] [PubMed] [Google Scholar]
  26. Spiegel A., Carter A., Brann M., Collins R., Goldsmith P., Simonds W., Vinitsky R., Eide B., Rossiter K., Weinstein L. Signal transduction by guanine nucleotide-binding proteins. Recent Prog Horm Res. 1988;44:337–375. doi: 10.1016/b978-0-12-571144-9.50015-6. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES