title: The vasoactive peptide adrenomedullin is secreted by adipocytes and inhibits lipolysis through NO-mediated beta-adrenergic agonist oxidation.
abstract: Adipocytes are known to secrete a number of adipokines, but many adipocyte secretions and their functional importance remain to be characterized. This work shows that human white adipocytes and 3T3-F442A-derived adipocytes produce adrenomedullin (AM) and that AM acts in an autocrine/paracrine way on lipid metabolism by extracellular inactivation of isoproterenol, a beta-adrenergic agonist. AM is described as a counter-regulatory factor involved in the control of cardiovascular homeostasis. This peptide is believed to protect the heart from several complications implicated in obesity-linked cardiomorbidity, such as arterial hypertension, cardiac fibrosis, and decreased sinusal variability. The exact source of circulating AM remains a matter of debate, although endothelial and vascular smooth muscle cells seem to be important sites of production. We show that human adipose cells and 3T3-F442A-derived adipocytes express AM receptors and secrete AM. The function of this feature was investigated in 3T3-F442A cell line at the level of lipolysis regulation. AM inhibited beta-adrenergic-stimulated lipolysis by a nitric oxide (NO)-dependent mechanism, inducing a significant decrease in pD2 value for isoproterenol (8.6 +/- 0.2 vs. 9.8 +/- 0.1, P<0.001). This effect is cGMP-independent since it occurred in the presence of the NO-sensitive guanylate cyclase inhibitor ODQ. It is apparently mediated by a novel extracellular mechanism. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrated that AM-produced NO oxidized isoproterenol to generate its aminochrome, namely isoprenochrome. Isoprenochrome amounts were increased 3.62 +/- 1.13-fold in cell culture media (P<0.05). We describe for the first time that AM down-regulates lipolysis in adipocytes through the chemical modification of a beta-agonist.
authors.affiliation: INSERM U586, Insitut Louis Bugnard, CHU Rangueil, Université Paul Sabatier, TSA 50032, Toulouse, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Harmancey
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Senard
authors.forename: Atul
authors.initials: A
authors.lastname: Pathak
authors.forename: Franck
authors.initials: F
authors.lastname: Desmoulin
authors.forename: Catherine
authors.initials: C
authors.lastname: Claparols
authors.forename: Philippe
authors.initials: P
authors.lastname: Rouet
authors.forename: Fatima
authors.initials: F
authors.lastname: Smih
mesh_terms: D017667:Adipocytes / Q000737:chemistry / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000378:metabolism*; D053607:Adrenomedullin; D000328:Adult; D002460:Cell Line; D002853:Chromatography, Liquid; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D007545:Isoproterenol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008066:Lipolysis / Q000502:physiology*; D008297:Male; D013058:Mass Spectrometry; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D010084:Oxidation-Reduction; D010455:Peptides / Q000378:metabolism* / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000318:Adrenergic beta-Agonists; D005230:Fatty Acids, Nonesterified; D006834:Hydrazines; C112653:PAPA NONOate; D010455:Peptides; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D053607:Adrenomedullin; D009569:Nitric Oxide; D007545:Isoproterenol