Sphingosine-1-phosphate modulates both lipolysis and leptin production in differentiated rat white adipocytes.
Sphingosine-1-phosphate (S1P) is a pluripotent lipid mediator that transmits signals through a family of G protein-coupled receptors to control diverse biological processes. Here, we investigated the effects of S1P on the levels of intracellular calcium and cAMP in differentiated rat white adipocytes and two important aspects of adipocyte-specific physiology, lipolysis and leptin production. In adipocytes, S1P signaling pathway was functionally linked to phospholipase C via pertussis-toxin-sensitive G protein. Interestingly, at higher S1P concentration (1-30 microM), it also induced cAMP generation in a concentration-dependent manner, which was pertussis toxin insensitive and was mimicked by dihydro-S1P and sphingosylphosphoryl-choline but not by its related metabolites, ceramide and sphingosine, or by its structural analogs, phyto-S1P and lysophosphatidic acid. Suramin, a known inhibitor of ligand-receptor interactions, reduced S1P-induced cAMP generation by 60% of control, whereas forskolin-induced cAMP increase was not affected by treatment with suramin. The S1P-induced cAMP generation was functionally linked to cAMP response element-binding protein phosphorylation. Finally, S1P significantly reduced insulin-induced mRNA of ob gene and leptin secretion, whereas S1P increased glycerol release from adipocytes. Both effects of S1P were reversed by a selective adenylyl cyclase inhibitor, SQ22536, without significantly affecting basal values. In conclusion, extracellular S1P elicits the elevation of cytosolic Ca2+ and cAMP with a distinct concentration dependency, and S1P-induced cAMP generation may be mediated by S1P-selective receptors rather than intracellular targets, and the activated adenylyl cyclase-cAMP signaling pathways subsequently increase lipolysis and decrease insulin-induced leptin production in rat white adipocytes.
Jun
Dong-Jae
DJ
Systems Bio-dynamics National Core Research Center, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Korea.
Lee
Jong-Hee
JH
Choi
Bo-Hwa
BH
Koh
Tae-Kyung
TK
Ha
Dae-Cheong
DC
Jeong
Min-Woo
MW
Kim
Kyong-Tai
KT
D000262:Adenylyl Cyclases / Q000502:physiology; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000096:biosynthesis*; D008066:Lipolysis / Q000187:drug effects*; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
D007295:Inositol Phosphates; D007328:Insulin; D020738:Leptin; D008246:Lysophospholipids; D020033:Protein Isoforms; D049349:Receptors, Lysosphingolipid; D014280:Triglycerides; C060506:sphingosine 1-phosphate; C052128:inositol 3-phosphate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D013110:Sphingosine; D002118:Calcium