Constitutive activation of the renin-angiotensin system reduces visceral fat and improves glucose tolerance in mice.

Abstract

The renin-angiotensin system (RAS), and particularly angiotensin II, is involved in the control of energy balance, glucose homeostasis and kidney functions. The integrated impact of the RAS on glucose homeostasis is still a matter of debate. We used a model of constitutive RAS activation in double transgenic mice (dTGM) carrying both human angiotensinogen and human renin genes. We evaluated energy balance, measured renal functions, performed glucose and insulin tolerance tests, and used ramipril to inhibit the angiotensin-converting enzyme. dTGM had a lower physical activity and an increased food intake without change in body weight. Renal impairment was characterized by low-grade albuminuria. High urinary output secondary to polydipsia was associated with proximal tubule dysfunction. Compared to controls, dTGM had a lower hyperglycemia induced by an intraperitoneal glucose administration. This decrease was not due to changes in insulin sensitivity and/or secretion. dTGM had an increased creatinine production and a lower epididymal fat mass. Acute inhibition of angiotensin-converting enzyme with ramipril did not suppress this improved glucose tolerance profile. Chronic RAS activation is not sufficient to cause insulin resistance in mice. Moreover, adaptation to constitutive RAS activation in mice results in a better glucose tolerance.