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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Functional and Pharmacological Characterization of the Natriuretic Peptide-Dependent Lipolytic Pathway in Human Fat Cells

Unité de recherches sur les obésités, Institut National de la Santé et de la Recherche Médicale U586, Institut Louis Bugnard, Centre Hospitalier Universitaire Rangueil, Université Paul Sabatier, Toulouse, France (C.M., J.G., C.S., F.C., M.L., M.B.); Department for Adaptation to Exercise (F.C.), and Department of Clinical and Medical Pharmacology (M.B.) Purpan Hospital, Toulouse, France

A lipolytic pathway involving natriuretic peptides has recently been discovered in human fat cells. Its functional characteristics and the interactions of the atrial natriuretic peptide (ANP)-induced effects with adrenergic and insulin pathways were studied. Characterization of the action of ANP antagonists, i.e., A71915, anantin, S-28-Y (Ser-28-Tyr, a synthesized peptide), and HS-142-1 (a microbial polysaccharide), was performed. Lipolytic assays and intracellular cGMP and cAMP determinations were performed on isolated fat cells. Cell membranes were used for binding studies. At low concentrations ANP and isoproterenol [-adrenergic receptor (-AR) agonist] exerted additive lipolytic effects. The ₂-AR pathway did not interfere with that of ANP. Lipolytic effects of ANP were unaltered by a 2-h pretreatment of fat cells with insulin, whereas -AR-induced lipolysis was reduced. Homologous desensitization occurred for ANP-dependent lipolytic pathways. Dendroapsis natriuretic peptide exhibited a similar maximal effect but a 10-fold higher lipolytic potency than ANP and mini-ANP (the shortest form of ANP). The antagonist A71915 exhibited competitive antagonistic properties with a pA₂ value of 7.51. Anantin displayed noncompetitive antagonism and exerted an inhibitory action on basal and -adrenergic receptor-induced lipolytic response. S-28-Y exhibited antagonist potencies toward ANP-induced lipolysis and behaved as a partial lipolytic agonist with a lower pD₂ value (7.4 ± 0.2) than ANP (9.4 ± 0.3). HS-142-1 exerted the weakest antagonistic effects. The results demonstrate that ANP-dependent effects do not interfere with - and ₂-adrenergic pathways in human fat cells. They are unaffected by insulin pretreatments of fat cells but undergo desensitization. In the search of potent and specific natriuretic peptide receptor-A antagonist, in the human fat cell, A71915 was the only reliable one found.

Address correspondence to: Dr. Max Lafontan, Unité INSERM 586, Institut Louis Bugnard, Hôpital Rangueil, 31403 Toulouse cedex 04, France. E-mail: Max.Lafontan{at}toulouse.inserm.fr

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