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The vasoactive peptide adrenomedullin is secreted by adipocytes and inhibits lipolysis through NO‐mediated β‐adrenergic agonist oxidation
Author(s) -
Harmancey Romain,
Senard JeanMichel,
Pathak Atul,
Desmoulin Franck,
Claparols Catherine,
Rouet Philippe,
Smih Fatima
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2868fje
Subject(s) - adrenomedullin , endocrinology , medicine , lipolysis , autocrine signalling , adipocyte , paracrine signalling , chemistry , adipose tissue , extracellular , receptor , biology , biochemistry
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 β‐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 β‐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 β‐agonist.