Chronic AT blockade improves hyperglycemia by decreasing adipocyte inflammation and decreasing hepatic PCK1 and G6PC1 expression in obese rats.

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT. We measured adipocyte morphology along with TNF-α expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before (), 60 () and 120 () min after an acute glucose challenge in the following groups of male rats: ) Long-Evans Tokushima Otsuka (LETO; lean control; = 5/time point), ) obese Otsuka Long Evans Tokushima Fatty (OLETF; = 7 or 8/time point), and ) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; = 7 or 8/time point). AT blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at , IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT blockade decreased hepatic and mRNA expressions. Collectively, these results suggest that chronic AT blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis. Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic and mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.