Differential effects of angiotensin II type 2 receptor antagonism in mice models of obesity

Angiotensin II ( ang II) is a vasoactive hormone derived from the renin angiotensin system (RAS), which regulates blood pressure and fluid balance in the body. Ang II effects are mediated via two major receptors: type 1 (AT 1) and type 2 (AT 2). Adipocytes contain a local RAS in which ang II upregulates adipogenesis, fatty acid and triglyceride synthesis primarily mediated via the AT 2 receptor in cultured adipocytes. Preliminary studies from our lab tested the importance of AT 2 receptors in vivo and reported a decrease in adiposity by AT 2 antagonism in the lean, but not the genetically obese db/db mouse. To further explore these effects, we used another genetic model of obesity (ob/ob) and diet-induced obese (DIO) mice and treated them for 2-3 weeks with the AT 2 receptor antagonist, PD 123,319. Body weight, fat pad weight and plasma glucose, leptin and insulin levels and fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPDH) activity were measured. Consistent with previous findings in lean mice, the AT 2 antagonist decreased abdominal fat pad weight in ob/ob mice and accelerated weight loss in D10 mice. Also, correlated with these effects, AT2 blockade decreased FAS activity in ob/ob mice and lowered blood glucose levels in DIO mice. No significant changes were seen in the other parameters that were measured. In combination with recently published data, this research further supports the role of the AT 2 receptor in modulating ang II effects on adipocyte metabolism. Defining this role is crucial in determining and preventing the contribution of adipocyte-derived RAS to systemic disorders such as obesity-related hypertension.