Sphingosine, an Inhibitor of Protein Kinase C, Suppresses the Insulin-like Effects of Growth Hormone in Rat Adipocytes

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1989 Jun 1

PMID 2660145

Citations 12

Authors

J Smal

P De Meyts

Affiliations

Soon will be listed here.

Abstract

Insulin, human growth hormone (hGH), and phorbol 12-myristate 13-acetate all stimulate lipogenesis in rat adipocytes preincubated without hGH for 4 hr. As previous data suggested that protein kinase C plays an important role in the action of insulin and in the insulin-like effects of hGH in rat adipocytes, we tested the effects of sphingosine, a potent inhibitor of protein kinase C, on the lipogenic activity of both hormones. At 50 microM, sphingosine had no effect on basal lipogenesis but completely abolished the action of phorbol 12-myristate 13-acetate and decreased by 65% and 89%, respectively, the effects of hGH and insulin. At higher concentrations (100 microM), sphingosine abolished both basal and hormone-stimulated lipogenesis; this effect was partially reversible after washing the cells. Similar effects of sphingosine on basal and stimulated glucose uptake were seen in parallel, suggesting that sphingosine inhibits lipogenesis at the glucose-uptake step in rat adipocytes. N-Acetylsphingosine and sphingomyelin, two analogs of sphingosine that are inactive on protein kinase C, did not inhibit lipogenesis induced by hGH, insulin, or phorbol 12-myristate 13-acetate. Sphingosine did not inhibit insulin binding to rat adipocytes at concentrations up to 200 microM but decreased hGH binding to its receptors by 44% at 50 microM. These data suggest a direct link between the inhibition of protein kinase C and that of lipogenesis and provide new evidence for the involvement of protein kinase C in the mechanism of action of growth hormone and insulin in rat adipocytes.

Citing Articles

Mechanisms of Insulin Action and Insulin Resistance.

Petersen M, Shulman G Physiol Rev. 2018; 98(4):2133-2223.

PMID: 30067154 PMC: 6170977. DOI: 10.1152/physrev.00063.2017.

PGC-1α improves glucose homeostasis in skeletal muscle in an activity-dependent manner.

Summermatter S, Shui G, Maag D, Santos G, Wenk M, Handschin C Diabetes. 2012; 62(1):85-95.

PMID: 23086035 PMC: 3526021. DOI: 10.2337/db12-0291.

High fat diet induced hepatic steatosis and insulin resistance: Role of dysregulated ceramide metabolism.

Longato L, Tong M, Wands J, de la Monte S Hepatol Res. 2011; 42(4):412-27.

PMID: 22176347 PMC: 4096625. DOI: 10.1111/j.1872-034X.2011.00934.x.

Lipid signalling in pathogenic fungi.

Singh A, Del Poeta M Cell Microbiol. 2010; 13(2):177-85.

PMID: 21091925 PMC: 5142819. DOI: 10.1111/j.1462-5822.2010.01550.x.

Growth hormone and phorbol esters require specific protein kinase C isoforms to activate mitogen-activated protein kinases in 3T3-F442A cells.

Mackenzie S, Fleming I, Houslay M, Anderson N, Kilgour E Biochem J. 1997; 324 ( Pt 1):159-65.

PMID: 9164852 PMC: 1218412. DOI: 10.1042/bj3240159.

References

Glynn B, Colliton J, McDermott J, Witters L . Phorbol esters, but not insulin, promote depletion of cytosolic protein kinase C in rat adipocytes. Biochem Biophys Res Commun. 1986; 135(3):1119-25. DOI: 10.1016/0006-291x(86)91044-2. View

Farese R, Barnes D, Davis J, Standaert M, Pollet R . 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; 259(11):7094-100. View

Farese R, KUO J, Babischkin J, Davis J . Insulin provokes a transient activation of phospholipase C in the rat epididymal fat pad. J Biol Chem. 1986; 261(19):8589-92. View

Saltiel A, Fox J, Sherline P, Cuatrecasas P . Insulin-stimulated hydrolysis of a novel glycolipid generates modulators of cAMP phosphodiesterase. Science. 1986; 233(4767):967-72. DOI: 10.1126/science.3016898. View

Nelson D, Murray D . Sphingolipids inhibit insulin and phorbol ester stimulated uptake of 2-deoxyglucose. Biochem Biophys Res Commun. 1986; 138(1):463-7. DOI: 10.1016/0006-291x(86)90303-7. View

Hidaka H, Inagaki M, Kawamoto S, Sasaki Y . Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984; 23(21):5036-41. DOI: 10.1021/bi00316a032. View

Takayama S, White M, LAURIS V, Kahn C . Phorbol esters modulate insulin receptor phosphorylation and insulin action in cultured hepatoma cells. Proc Natl Acad Sci U S A. 1984; 81(24):7797-801. PMC: 392239. DOI: 10.1073/pnas.81.24.7797. View

Trevillyan J, Perisic O, Traugh J, Byus C . Insulin- and phorbol ester-stimulated phosphorylation of ribosomal protein S6. J Biol Chem. 1985; 260(5):3041-4. View

Ullrich A, Bell J, Chen E, Herrera R, Petruzzelli L, Dull T . Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985; 313(6005):756-61. DOI: 10.1038/313756a0. View

10.

van de Werve G, Proietto J, Jeanrenaud B . Tumour-promoting phorbol esters increase basal and inhibit insulin-stimulated lipogenesis in rat adipocytes without decreasing insulin binding. Biochem J. 1985; 225(2):523-7. PMC: 1144619. DOI: 10.1042/bj2250523. View

11.

Hannun Y, Loomis C, Merrill Jr A, Bell R . Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J Biol Chem. 1986; 261(27):12604-9. View

12.

Merrill Jr A, Sereni A, Stevens V, Hannun Y, Bell R, KINKADE Jr J . Inhibition of phorbol ester-dependent differentiation of human promyelocytic leukemic (HL-60) cells by sphinganine and other long-chain bases. J Biol Chem. 1986; 261(27):12610-5. View

13.

Wilson E, Olcott M, Bell R, Merrill Jr A, Lambeth J . Inhibition of the oxidative burst in human neutrophils by sphingoid long-chain bases. Role of protein kinase C in activation of the burst. J Biol Chem. 1986; 261(27):12616-23. View

14.

Rodriguez-Pena A, Rozengurt E . Vasopressin rapidly stimulates protein kinase C in quiescent Swiss 3T3 cells. J Cell Physiol. 1986; 129(1):124-30. DOI: 10.1002/jcp.1041290117. View

15.

Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E . The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling. Cell. 1985; 40(4):747-58. DOI: 10.1016/0092-8674(85)90334-4. View

16.

Kahn C . The molecular mechanism of insulin action. Annu Rev Med. 1985; 36:429-51. DOI: 10.1146/annurev.me.36.020185.002241. View

17.

Isaksson O, Eden S, Jansson J . Mode of action of pituitary growth hormone on target cells. Annu Rev Physiol. 1985; 47:483-99. DOI: 10.1146/annurev.ph.47.030185.002411. View

18.

Kirsch D, Obermaier B, Haring H . Phorbolesters enhance basal D-glucose transport but inhibit insulin stimulation of D-glucose transport and insulin binding in isolated rat adipocytes. Biochem Biophys Res Commun. 1985; 128(2):824-32. DOI: 10.1016/0006-291x(85)90121-4. View

19.

Farese R, Standaert M, Barnes D, Davis J, Pollet R . Phorbol ester provokes insulin-like effects on glucose transport, amino acid uptake, and pyruvate dehydrogenase activity in BC3H-1 cultured myocytes. Endocrinology. 1985; 116(6):2650-5. DOI: 10.1210/endo-116-6-2650. View

20.

Skoglund G, Hansson A, Ingelman-Sundberg M . Rapid effects of phorbol esters on isolated rat adipocytes. Relationship to the action of protein kinase C. Eur J Biochem. 1985; 148(3):407-12. DOI: 10.1111/j.1432-1033.1985.tb08854.x. View