{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Dominici FP"],"funding":["American Heart Association","NIDDK NIH HHS","National Institute of Diabetes and Digestive and Kidney Diseases","NIAID NIH HHS","National Heart, Lung, and Blood Institute","NHLBI NIH HHS","Universidad de Buenos Aires","Fondo para la Investigación Científica y Tecnológica"],"pagination":["4766-4781"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7520448"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["177(20)"],"pubmed_abstract":["<h4>Background and purpose</h4>The AT<sub>2</sub> receptor plays a role in metabolism by opposing the actions triggered by the AT<sub>1</sub> receptors. Activation of AT<sub>2</sub> receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT<sub>2</sub> receptors activation improves metabolism in diabetic mice.<h4>Experimental approach</h4>Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT<sub>2</sub> agonist, compound 21 (C21, 0.3 mg·kg<sup>-1</sup> ·day<sup>-1</sup> , s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub-pressor dose of the NOS inhibitor l-NAME (0.1 mg·ml<sup>-1</sup> , drinking water).<h4>Key results</h4>C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline-treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared with saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT<sub>2</sub> receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l-NAME.<h4>Conclusion and implications</h4>Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production."],"journal":["British journal of pharmacology"],"pubmed_title":["Activation of AT<sub>2</sub> receptors prevents diabetic complications in female db/db mice by NO-mediated mechanisms."],"pmcid":["PMC7520448"],"funding_grant_id":["R01 AI134714","R01 AI132599","UBACYT 20020130100218BA","T32 DK007770","R01HL142672","16SDG30130015","P01HL129941","PICT‐2014‐0362","R01 HL142672","P30DK063491","P01 HL129941","PICT-2014-0362","17GRNT33661206","P30 DK063491"],"pubmed_authors":["Bernstein KE","Dominici FP","Bernstein EA","Quiroga DT","Giani JF","Shen JZY","Steckelings UM","Veiras LC"],"additional_accession":[]},"is_claimable":false,"name":"Activation of AT<sub>2</sub> receptors prevents diabetic complications in female db/db mice by NO-mediated mechanisms.","description":"<h4>Background and purpose</h4>The AT<sub>2</sub> receptor plays a role in metabolism by opposing the actions triggered by the AT<sub>1</sub> receptors. Activation of AT<sub>2</sub> receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT<sub>2</sub> receptors activation improves metabolism in diabetic mice.<h4>Experimental approach</h4>Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT<sub>2</sub> agonist, compound 21 (C21, 0.3 mg·kg<sup>-1</sup> ·day<sup>-1</sup> , s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub-pressor dose of the NOS inhibitor l-NAME (0.1 mg·ml<sup>-1</sup> , drinking water).<h4>Key results</h4>C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline-treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared with saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT<sub>2</sub> receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l-NAME.<h4>Conclusion and implications</h4>Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Oct","modification":"2025-04-26T02:00:29.722Z","creation":"2022-02-11T11:33:54.875Z"},"accession":"S-EPMC7520448","cross_references":{"pubmed":["32851652"],"doi":["10.1111/bph.15241"]}}