title: Evidence for a role of protein kinase C in the stimulation of lipolysis by growth hormone and isoproterenol.
abstract: The mechanism that underlies activation of lipolysis by GH is not yet understood. Although cAMP is thought to be involved, the biochemical linkages between GH and cAMP are unknown, and lipolysis produced by GH differs from that produced by such typical activators of adenylate cyclase as the catecholamines with regard to time course, maximum response, and dependence on other factors such as glucocorticoids or theophylline. The present studies were undertaken to evaluate the possibility that activation of protein kinase C by GH may play an important role in the production of the delayed increase in lipolysis. Phorbol myristate acetate (PMA), a known activator of protein kinase C, increased lipolysis in segments of adipose tissue of hypophysectomized rats, and, as with GH, this effect was potentiated by theophylline. The lipolytic effects of PMA were concentration-dependent, required a shorter lag period than those of human GH, increased as the concentration of PMA was raised from 0.1 to 10 microM, and were additive at all concentrations with lipolysis produced by saturating concentrations of GH. The lipolytic actions of GH, but not PMA, were potentiated by dexamethasone in adipose tissue of normal rats. Sphingosine and staurosporine, which are known to inhibit protein kinase C, blocked the lipolytic effects of PMA and severely reduced lipolysis in response to GH in tissues of both normal and hypophysectomized rats. Although higher concentrations of sphingosine interfered with the specific binding of 125I-labeled human GH to isolated adipocytes, the inhibitory effects of sphingosine cannot be attributed to interference with GH binding, since it decreased lipolysis by at least 50% when used at concentrations that were too low to reduce binding significantly. Staurosporine produced little (approximately 20%) or no decrease in binding. At concentrations that severely reduced lipolysis in response to GH and dexamethasone, sphingosine had little or no effect on lipolysis in response to dibutyryl cAMP or forskolin. Staurosporine and sphingosine, however, severely inhibited lipolysis in response to isoproterenol. We conclude that protein kinase C activity plays an important role in hormone-stimulated lipolysis probably by an action exerted on the transduction pathway proximal to cAMP. The present data are equally consistent with the possibilities that GH and/or isoproterenol activate protein kinase C, or that protein kinase C is constitutively active to some extent. It is likely that protein kinase C activity is permissive for, rather than a mediator of, the lipolytic actions of GH and isoproterenol.
authors.affiliation: Department of Physiology, University of Massachusetts Medical School, Worcester 01605.
authors.forename: E
authors.initials: E
authors.lastname: Gorin
authors.forename: L R
authors.initials: LR
authors.lastname: Tai
authors.forename: T W
authors.initials: TW
authors.lastname: Honeyman
authors.forename: H M
authors.initials: HM
authors.lastname: Goodman
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D013006:Growth Hormone / Q000494:pharmacology*; D007016:Hypophysectomy; D007545:Isoproterenol / Q000494:pharmacology*; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D013110:Sphingosine / Q000494:pharmacology; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D003994:Bucladesine; D003907:Dexamethasone; D013006:Growth Hormone; D013806:Theophylline; D011493:Protein Kinase C; D019311:Staurosporine; D007545:Isoproterenol; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate