title: The imidazoline I2-site ligands BU 224 and 2-BFI inhibit MAO-A and MAO-B activities, hydrogen peroxide production, and lipolysis in rodent and human adipocytes.
abstract: Numerous imidazolinic agents exhibit antihyperglycaemic properties and have been described to promote insulin secretion, however their effects on adipose tissue development have been poorly investigated. Since white adipose tissue (WAT) plays an important role in glucose homeostasis and expresses imidazoline (I(2)) binding sites abundantly, this work aimed at studying extrapancreatic actions of two I(2)-site ligands, BU 224 and 2-BFI in adipocytes. Interaction with monoamine oxidase (MAO) was investigated by measuring the ability to modulate [(14)C]tyramine oxidation and hydrogen peroxide production. Direct influence on glucose uptake or on lipolytic activity was tested on mouse, rat, rabbit and human adipocytes. BU 224 and 2-BFI behaved as reversible inhibitors of both MAO-A and -B, as demonstrated by total inhibition of tyramine oxidation in human adipocytes and platelets or in liver from rats previously treated with selective MAO-inhibitors. Moreover, they weakly inhibited semicarbazide-sensitive amine oxidase. Like classical MAO-inhibitors, they were unable to produce hydrogen peroxide and to activate glucose uptake but prevented tyramine to do so in rodent or human adipocytes. BU 224 and 2-BFI also differed from MAO-inhibitors since they inhibited lipolysis at millimolar concentrations via a still undefined pathway independent of alpha(2)-adrenoceptor stimulation, beta-adrenergic antagonism and MAO activation. However, chronic treatment of obese Zucker rats with 2-BFI did not modify the maximal lipolytic capacity or the mild insulin resistance status of their adipocytes. Taken together, our observations demonstrate on WAT novel effects of BU 224 and 2-BFI different from their already reported actions on brain or endocrine pancreas.
authors.affiliation: Inserm, U586, Unité de Recherches sur les Obésités, Université Paul Sabatier, IFR31, CHU Rangueil, Toulouse, F-31432, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Bour
authors.forename: María-Carmen
authors.initials: MC
authors.lastname: Iglesias-Osma
authors.forename: Luc
authors.initials: L
authors.lastname: Marti
authors.forename: Piedad
authors.initials: P
authors.lastname: Duro
authors.forename: María-José
authors.initials: MJ
authors.lastname: Garcia-Barrado
authors.forename: Maria-Francisca
authors.initials: MF
authors.lastname: Pastor
authors.forename: Danielle
authors.initials: D
authors.lastname: Prévot
authors.forename: Virgile
authors.initials: V
authors.lastname: Visentin
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.forename: Julio
authors.initials: J
authors.lastname: Moratinos
authors.forename: Christian
authors.initials: C
authors.lastname: Carpéné
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000493:pharmacokinetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D048288:Imidazolines / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker
chemical_list: C105826:BU 224; D001572:Benzofurans; D007093:Imidazoles; D048288:Imidazolines; D008996:Monoamine Oxidase Inhibitors; C103723:2-(2-benzofuranyl)-2-imidazoline; D006861:Hydrogen Peroxide; D006631:Amine Oxidase (Copper-Containing); D008995:Monoamine Oxidase; D005947:Glucose