Genetic Ablation of The Ren1c and Leptin Genes Improves Insulin and Leptin Sensitivity in Mice

Abstract

It is well-recognized that the activation of the renin-angiotensin system (RAS) and leptin resistance are implicated in the pathogenesis of obesity and type 2 diabetes. Indeed, we have previously demonstrated that the mice lacking the renin (Ren1c-/-) gene are lean and insulin sensitive, which were associated with increased energy expenditure and fecal fat excretion. We further showed that the expression of the suppressor of cytokine signaling 3 (SOCS3), a molecule that contributes to leptin resistance, was significantly decreased in Ren1c-/- mice. In the present study, we tested the hypothesis that genetic deletion of Ren1c or blockade of angiotensin II (Ang II) AT1 receptors improves leptin and insulin sensitivity in mice. To test the hypothesis, male wild-type (WT) and Ren1c-/- mice were infused with or without leptin (100 μg/kg/day, i.p.) for two weeks. Mice were subjected to intraperitoneal glucose tolerance (IPGTT) and insulin tolerance test (IPITT) at basal and after leptin treatment. The expression of p-STAT3 and AMPK was determined by western blot and ELISA. The expression of phosphorylated STAT3 proteins was significantly increased in the hypothalamus of Ren1c-/- mice than in WT mice (P<0.05), while AMPK activity of the hypothalamus was markedly decreased in Ren1c-/- mice (P<0.05). These responses in Ren1c-/- mice were recapitulated by the blockade of AT1 receptors with losartan (0.15 g/L in drinking water) in WT mice. We reasoned that these responses to leptin in Ren1c-/- mice may be due to decreased plasma leptin levels in Ren1c-/- mice. To further test this hypothesis, we generated mice lacking both renin and leptin (Ren1c-/-;ob/ob). Ren1c-/-;ob/ob mice had ~10% lower body weight than ob/ob mice under basal conditions, and their body weight and body fat decreased further in response to leptin infusion. More importantly, the hypothalamus of Ren1c-/-;ob/ob mice had significantly lower SOCS3 and AMPK activity and higher p-STAT3 expression compared to ob/ob mice (P<0.05). Glucose and insulin tolerance were significantly improved in Ren1c-/-;ob/ob mice, compared to ob/ob mice. Blockade of AT1 receptors with losartan also significantly improved IPGTT and IPITT, respectively. Taken together, our results suggest that the RAS plays an important role in both insulin and leptin resistance in obesity and type 2 diabetes, and that genetic deletion of Ren1c or blockade of angiotensin II (Ang II) AT1 receptors improves leptin and insulin sensitivity in ob/ob mice.