Abstract 042: Gender Differences in Response to Chronic Angiotensin-(1-7) Treatment in Obesity

Abstract

Angiotensin (Ang)-(1-7) is a vasodilatory hormone of the renin-angiotensin system (RAS) that has recently been shown to play a role in glucose homeostasis. Our previous study showed that obese male mice are deficient in circulating Ang-(1-7), and that chronic Ang-(1-7) restoration improves insulin sensitivity independent of blood pressure. Obese female mice also develop insulin resistance and glucose intolerance; however, the ability of Ang-(1-7) to improve metabolic function in females has not been explored. We hypothesized that Ang-(1-7) would equally improve glucose homeostasis in obese female and male mice. Adult male and female C57Bl/6J mice were placed on standard chow or 60% high fat diet (HFD) for 11 weeks, with Ang-(1-7) [400ng/kg/min] or saline given subcutaneously during the last 3 weeks of diet (n=8-12/group). During the last week of treatment, we assessed body composition and performed intraperitoneal insulin tolerance (ITT) and glucose tolerance (GTT) tests. While females had lower body mass throughout the study, both genders similarly increased adiposity in response to HFD (females: 7±1 chow vs 22±1% of body mass HFD; p=0.001; males: 6±1 vs 21±2% of body mass HFD, p=0.001). Ang-(1-7) had no effect on body composition in obese males, but reduced body mass (35±1 vs 31±2 g; p=0.028) and adiposity (22±1 vs 17±2% of body mass; p=0.024) and improved lean mass (p=0.019) in obese females. Ang-(1-7) improved insulin sensitivity in both obese male and female mice (p<0.001), with no gender differences (p=0.429). Ang-(1-7) improved glucose tolerance in obese female mice [area under the curve (AUC) for change in blood glucose levels during GTT: 20748±3156 chow vs 37582±2219 HFD vs 22884±5610 HFD+Ang-(1-7); p=0.044], with no effect in obese male mice (p=0.894). There was no effect of Ang-(1-7) on any outcome in chow fed male or female mice. Our data suggests that obese female mice are more responsive to chronic Ang-(1-7) therapy in terms of metabolic outcomes compared with obese male mice. These findings may have implications for understanding gender differences in RAS mechanisms involved in obesity and related metabolic complications.