title: Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance.
abstract: Altered adiponectin signaling and chronic sympathetic hyperactivity have both been proposed as key factors in the pathogenesis of metabolic syndrome. We recently reported that activation of I1 imidazoline receptors (I1R) improves several symptoms of the metabolic syndrome through sympathoinhibition and increases adiponectin plasma levels in a rat model of metabolic syndrome (Fellmann L, Regnault V, Greney H, et al. J Pharmacol Exp Ther 346: 370-380, 2013). The present study was designed to explore the peripheral component of the beneficial actions of I1R ligands (i.e., sympathoinhibitory independent effects). Aged rats displaying insulin resistance and glucose intolerance were treated with LNP509, a peripherally acting I1R agonist. Glucose tolerance, insulin sensitivity, and adiponectin signaling were assessed at the end of the treatment. Direct actions of the ligand on hepatocyte and adipocyte signaling were also studied. LNP509 reduced the area under the curve of the intravenous glucose tolerance test and enhanced insulin hypoglycemic action and intracellular signaling (Akt phosphorylation), indicating improved glucose tolerance and insulin sensitivity. LNP509 stimulated adiponectin secretion acting at I1R on adipocytes, resulting in increased plasma levels of adiponectin; it also enhanced AMPK phosphorylation in hepatic tissues. Additionally, I1R activation on hepatocytes directly enhanced AMPK phosphorylation. To conclude, I1R ligands can improve insulin sensitivity acting peripherally, independently of sympathoinhibition; stimulation of adiponectin and AMPK pathways at insulin target tissues may account for this effect. This may open a promising new way for the treatment of the metabolic syndrome.
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, France;
authors.forename: Maud
authors.initials: M
authors.lastname: Weiss
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, France;
authors.forename: Soumaya
authors.initials: S
authors.lastname: Bouchoucha
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, France;
authors.forename: Farouk
authors.initials: F
authors.lastname: Aiad
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, France;
authors.forename: Estelle
authors.initials: E
authors.lastname: Ayme-Dietrich
authors.affiliation: Laboratoire de Biochimie Générale et Spécialisée, Hôpitaux Universitaires, Strasbourg, France; and Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS UMR 7104/INSERM U964, Université de Strasbourg, Illkirch, France.
authors.forename: Nassim
authors.initials: N
authors.lastname: Dali-Youcef
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, France;
authors.forename: Pascal
authors.initials: P
authors.lastname: Bousquet
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, France;
authors.forename: Hugues
authors.initials: H
authors.lastname: Greney
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, Université de Strasbourg, France; nathalie.niederhoffer@unistra.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Niederhoffer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018149:Glucose Intolerance / Q000378:metabolism* / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D048288:Imidazolines / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D052242:Adiponectin; D048288:Imidazolines; D055372:AMP-Activated Protein Kinases
keywords: I1 imidazoline receptors; adiponectin and AMPK signaling; glucose tolerance; insulin resistance; metabolic syndrome; sympathetic tone