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Chronic AT1 blockade improves hyperglycemia by decreasing adipocyte inflammation and decreasing hepatic PCK1 and
Ruben Rodriguez1, Andrew Y Lee1, Jose A Godoy-Lugo1
1Department of Molecular & Cellular Biology, University of California, Merced, California.
Abstract:
Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT1) 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 AT1 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 AT1. 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 (T0), 60 (T60) and 120 (T120) min after an acute glucose challenge in the following groups of male rats: 1) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT1 blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60, IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT1 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 AT1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis.NEW & NOTEWORTHY Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic Pck1 and G6pc1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.
Insights
Chronic angiotensin receptor type 1 (AT1) blockade improves hyperglycemia by enhancing adipocyte function and reducing hepatic glucose production. This treatment in obese rats improved glucose uptake and reduced inflammation in adipose tissue.
Area of Science:
- Endocrinology and Metabolism
- Cardiovascular Physiology
- Obesity Research
Background:
- Inappropriate activation of the renin-angiotensin system (RAS) impairs glucose uptake in peripheral tissues, contributing to hyperglycemia.
- Chronic angiotensin receptor type 1 (AT1) blockade (ARB) is known to improve glucose uptake in skeletal muscle and reduce adipocyte size and inflammation.
Purpose of the Study:
- To determine the specific contributions of soleus muscle, liver, and adipose tissue to the overall improvement in hyperglycemia following chronic AT1 blockade.
- To investigate the static and dynamic responses of these tissues to an acute glucose challenge after AT1 blockade in obese rats.
Main Methods:
- Male Otsuka Long Evans Tokushima Fatty (OLETF) rats (obese) and Long-Evans Tokushima Otsuka (LETO) rats (lean control) were used.
- Groups included LETO, OLETF, and OLETF treated with ARB (olmesartan).
- Measurements included adipocyte morphology, TNF-α expression, macrophage infiltration (F4/80, CD11c), insulin receptor (IR) and AKT phosphorylation, and hepatic gluconeogenic gene expression (Pck1, G6pc1) at baseline and after an acute glucose challenge.
Main Results:
- AT1 blockade significantly reduced adipocyte TNF-α expression and macrophage infiltration in OLETF rats.
- In retroperitoneal fat, ARB treatment increased IR phosphorylation and glucose transporter-4 (GLUT4) protein expression compared to untreated OLETF rats.
- While hepatic IR and AKT phosphorylation were unchanged, AT1 blockade decreased hepatic Pck1 and G6pc1 mRNA expression, indicating reduced gluconeogenesis.
Conclusions:
- Chronic AT1 blockade ameliorates obesity-associated hyperglycemia in OLETF rats.
- Improvements are driven by enhanced adipocyte function (reduced inflammation, increased glucose uptake) and decreased hepatic glucose production via gluconeogenesis.
- These findings highlight the role of RAS in adipose tissue inflammation and hepatic glucose regulation, contributing to glucose intolerance.
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