biostudies-literatureDominici FPAmerican Heart AssociationNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNIAID NIH HHSNational Heart, Lung, and Blood InstituteNHLBI NIH HHSUniversidad de Buenos AiresFondo para la Investigación Científica y Tecnológica4766-4781https://www.ebi.ac.uk/biostudies/studies/S-EPMC7520448biostudies-literatureUnknown177(20)<h4>Background and purpose</h4>The AT₂ receptor plays a role in metabolism by opposing the actions triggered by the AT₁ receptors. Activation of AT₂ 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 AT₂ 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 AT₂ agonist, compound 21 (C21, 0.3 mg·kg^-1 ·day^-1 , 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^-1 , 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 AT₂ 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.British journal of pharmacologyActivation of AT₂ receptors prevents diabetic complications in female db/db mice by NO-mediated mechanisms.PMC7520448R01 AI134714R01 AI132599UBACYT 20020130100218BAT32 DK007770R01HL14267216SDG30130015P01HL129941PICT‐2014‐0362R01 HL142672P30DK063491P01 HL129941PICT-2014-036217GRNT33661206P30 DK063491Bernstein KEDominici FPBernstein EAQuiroga DTGiani JFShen JZYSteckelings UMVeiras LCfalseActivation of AT₂ receptors prevents diabetic complications in female db/db mice by NO-mediated mechanisms.<h4>Background and purpose</h4>The AT₂ receptor plays a role in metabolism by opposing the actions triggered by the AT₁ receptors. Activation of AT₂ 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 AT₂ 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 AT₂ agonist, compound 21 (C21, 0.3 mg·kg^-1 ·day^-1 , 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^-1 , 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 AT₂ 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.2020-01-01T00:00:00Z2020 Oct2025-04-26T02:00:29.722Z2022-02-11T11:33:54.875ZS-EPMC75204483285165210.1111/bph.15241