MAS DEFICIENCY IN FVB/N MICE PRODUCES MARKED CHANGES IN LIPID AND GLYCEMIC METABOLISM

Abstract

Objective: Metabolic syndrome is characterized by the variable coexistence of obesity, hyperinsulinemia, insulin resistance, dyslipidemia, and hypertension. It is well known that angiotensin II is importantly involved in metabolic syndrome. However, the role of the vasodilator angiotensin-(1-7)/Mas axis is not known. The aim of this study was to evaluate the effect of genetic deletion of G protein-coupled receptor, Mas, in the lipidic and glycemic metabolism in FVB/N mice.

Research Design and Methods: Plasma lipids, insulin and cytokines concentrations were measured in FVB/N Mas-deficient and wild type mice. A glucose-tolerance test was performed by intraperitoneally injecting D-glucose into overnight fasted mice. Insulin sensitivity test was performed by intraperitoneal injection of insulin. Uptake of 2-deoxy-[3H]glucose by adipocytes was used to determine the rate of glucose transport; adipose tissue GLUT4 was quantified by Western blot. Gene expression of TGF-β, AT1R and angiotensinogen were measured by real time PCR.

Results: Despite of normal body weight, Mas-knockout mice presented dyslipidemia, increased levels of insulin and leptin, and ∼50% increase in abdominal fat mass. In addition, Mas-gene deleted mice presented glucose intolerance and reduced insulin sensitivity as well as a decrease in insulin-stimulated glucose uptake by adipocytes and decreased GLUT4 in adipose tissue. Mas^−/− presented increased muscle triglycerides while liver triglycerides level was normal. Expression of TGF-β and angiotensinogen genes was higher in Mas-knockout animals in comparison to controls.

Conclusions: These results show that Mas-deficiency in FVB/N mice leads to dramatic changes in glucose and lipid metabolisms, inducing a metabolic syndrome-like state.