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Published on: November 16, 2011
Chronic blockade of the AT2 receptor with PD123319 impairs insulin signaling in C57BL/6 mice
M C Muñoz1, V Burghi1, J G Miquet1
1Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires IQUIFIB-CONICET, Junín 956, 6to piso, 1113 Buenos Aires, Argentina.
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.
Insights
The angiotensin type 2 receptor (AT2R) plays a crucial role in maintaining insulin sensitivity. Blocking AT2R impairs insulin signaling in the liver and adipose tissue, highlighting its protective function against insulin resistance.
Area of Science:
- Endocrinology
- Metabolic Research
- Cardiovascular Physiology
Background:
- The renin-angiotensin system influences insulin action, with Angiotensin type 1 receptor (AT1R) showing detrimental effects.
- Angiotensin type 2 receptor (AT2R) is implicated in beneficial effects, potentially protecting against insulin resistance and type 2 diabetes.
- Existing research on AT2R's role in insulin sensitivity presents conflicting findings, necessitating further investigation.
Purpose of the Study:
- To elucidate the specific role of the Angiotensin type 2 receptor (AT2R) in regulating insulin action.
- To investigate the impact of AT2R blockade on glucose homeostasis and insulin signaling pathways.
Main Methods:
- C57Bl/6 mice were treated with the synthetic AT2R antagonist PD123319 (10mg/kg/day ip) for 21 days.
- Control groups received vehicle treatment.
- Evaluated parameters included glucose tolerance, metabolic profiles, insulin signaling (insulin receptor and Akt phosphorylation) in liver, adipose tissue, and skeletal muscle, and inflammatory markers (adiponectin, TNF-α, MCP-1, IL-6) in adipose tissue.
Main Results:
- AT2R blockade with PD123319 resulted in minimal changes to overall glucose homeostasis.
- Significant reduction in insulin-induced phosphorylation of the insulin receptor and Akt was observed in the liver and adipose tissue.
- Insulin signaling in skeletal muscle remained unaffected by PD123319 treatment.
Conclusions:
- The Angiotensin type 2 receptor (AT2R) is vital for preserving insulin action, particularly in the liver and adipose tissue.
- Impaired insulin signaling in key metabolic tissues following AT2R blockade underscores its physiological importance.
- These findings support a protective role for AT2R in maintaining metabolic health and preventing insulin resistance.
