Abstract
The renin–angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effect, whereas the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. To further explore the role of the AT2R on insulin action and glucose homeostasis, in this study we administered C57Bl/6 mice with the synthetic agonist of the AT2R C21 for 12 weeks (1 mg/kg per day; ip). Vehicle‐treated animals were used as control. Metabolic parameters, glucose, and insulin tolerance, in vivo insulin signaling in main insulin‐target tissues as well as adipose tissue levels of adiponectin, and TNF‐α were assessed. C21‐treated animals displayed decreased glycemia together with unaltered insulinemia, increased insulin sensitivity, and increased glucose tolerance compared to nontreated controls. This was accompanied by a significant decrease in adipocytes size in epididymal adipose tissue and significant increases in both adiponectin and UCP‐1 expression in this tissue. C21‐treated mice showed an increase in both basal Akt and ERK1/2 phosphorylation levels in the liver, and increased insulin‐stimulated Akt activation in adipose tissue. This positive modulation of insulin action induced by C21 appeared not to involve the insulin receptor. In C21‐treated mice, adipose tissue and skeletal muscle became unresponsive to insulin in terms of ERK1/2 phosphorylation levels. Present data show that chronic pharmacological activation of AT2R with C21 increases insulin sensitivity in mice and indicate that the AT2R has a physiological role in the conservation of insulin action.
Highlights
Given that the enhanced insulin sensitivity and glucose tolerance observed after Compound 21 (C21) treatment was associated with decreased adipocyte size, we performed further evaluation of adipose tissue status
Our findings show that C57BL/6 mice exposed to chronic, systemic pharmacological angiotensin type 2 receptor (AT2R) agonism with C21 display decreased glycemia, enhanced glucose tolerance, and improved insulin sensitivity, suggesting an active role of the AT2R in the modulation of glycemic control under physiological conditions
Improvement of glucose homeostasis is associated with an activation of Akt and ERK1/2 under basal conditions in the liver and with an enhancement of insulin-induced Akt activation in adipose tissue
Summary
The renin–angiotensin system (RAS) is an important endocrine system that regulates renal, cardiac, and vascular physiology, either by system effects via the circulation, or via local effects within tissues (Ferrario et al 2014; Karnik et al 2015; Carey 2017). Most of the actions of Ang II are mediated by the AT1R (Booz and Baker 1996; Jones et al 2008; Karnik et al 2015; Carey 2017; Padia and Carey 2013). Its expression declines quickly during the neonatal period showing a relatively low expression compared to AT1Rs in most adult tissues (Ferrario et al 2014; Karnik et al 2015; Carey 2017). The modulation of the counterbalance between AT1Rs and AT2Rs has an important therapeutic implication in pathological conditions such as atherosclerosis, insulin resistance, diabetes mellitus, nephropathy, and pulmonary fibrosis (Padia and Carey 2013; Paulis et al 2016)
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