title: Chronic blockade of the AT2 receptor with PD123319 impairs insulin signaling in C57BL/6 mice.
abstract: The renin-angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effects while the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. Although recent reports indicate that agonism of AT2R ameliorates diabetes and insulin resistance, the phenotype of AT2R-knockout mice seems to be controversial relating this aspect. Thus, in this study we have explored the role of AT2R in the control of insulin action. To that end, C57Bl/6 mice were administered the synthetic AT2R antagonist PD123319 for 21days (10mg/kg/day ip); vehicle treated animals were used as control. Glucose tolerance, metabolic parameters, in vivo insulin signaling in main insulin-target tissues as well as levels of adiponectin, TNF-α, MCP-1 and IL-6 in adipose tissue were assessed. AT2R blockade with PD123319 induced a marginal effect on glucose homeostasis but an important reduction in the insulin-induced phosphorylation of the insulin receptor and Akt in both liver and adipose tissue. Insulin signaling in skeletal muscle remained unaltered after treatment with PD123319, which could explain the minimal effect on glucose homeostasis induced by PD123319. Our current results reinforce the notion that the AT2R has a physiological role in the conservation of insulin action.
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires IQUIFIB-CONICET, Junín 956, 6to piso, 1113 Buenos Aires, Argentina.
authors.forename: M C
authors.initials: MC
authors.lastname: Muñoz
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires IQUIFIB-CONICET, Junín 956, 6to piso, 1113 Buenos Aires, Argentina.
authors.forename: V
authors.initials: V
authors.lastname: Burghi
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires IQUIFIB-CONICET, Junín 956, 6to piso, 1113 Buenos Aires, Argentina.
authors.forename: J G
authors.initials: JG
authors.lastname: Miquet
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires IQUIFIB-CONICET, Junín 956, 6to piso, 1113 Buenos Aires, Argentina.
authors.forename: I A
authors.initials: IA
authors.lastname: Cervino
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires IQUIFIB-CONICET, Junín 956, 6to piso, 1113 Buenos Aires, Argentina.
authors.forename: D T
authors.initials: DT
authors.lastname: Quiroga
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires IQUIFIB-CONICET, Junín 956, 6to piso, 1113 Buenos Aires, Argentina.
authors.forename: L
authors.initials: L
authors.lastname: Mazziotta
authors.affiliation: Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires IQUIFIB-CONICET, Junín 956, 6to piso, 1113 Buenos Aires, Argentina. Electronic address: dominici@qb.ffyb.uba.ar.
authors.forename: F P
authors.initials: FP
authors.lastname: Dominici
mesh_terms: D052242:Adiponectin / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D057912:Angiotensin II Type 2 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007093:Imidazoles / Q000008:administration & dosage; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D019808:Losartan / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000008:administration & dosage; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D052242:Adiponectin; D057912:Angiotensin II Type 2 Receptor Blockers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007093:Imidazoles; D007328:Insulin; D015850:Interleukin-6; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C073402:PD 123319; D019808:Losartan
keywords: Angiotensin II; Angiotensin type 2 receptor; Glucose tolerance; Insulin; Renin-angiotensin system