Sex differences in metabolic effects of angiotensin-(1-7) treatment in obese mice

Angiotensin-(1-7) is a beneficial hormone of the renin-angiotensin system known to play a positive role in regulation of blood pressure and glucose homeostasis. Previous studies have shown that in high-fat diet (HFD)-induced obese male mice, circulating angiotensin-(1-7) levels are reduced and chronic restoration of this hormone reverses diet-induced insulin resistance; however, this has yet to be examined in female mice. We hypothesized angiotensin-(1-7) would improve insulin sensitivity and glucose tolerance in obese female mice, to a similar extent as previously observed in male mice. Five-week-old male and female C57BL/6J mice (8-12/group) were placed on control diet or HFD (16% or 59% kcal from fat, respectively) for 11 weeks. After 8 weeks of diet, mice were implanted with an osmotic pump for 3-week subcutaneous delivery of angiotensin-(1-7) (400 ng/kg/min) or saline vehicle. During the last week of treatment, body mass and composition were measured and intraperitoneal insulin and glucose tolerance tests were performed to assess insulin sensitivity and glucose tolerance, respectively. Mice were euthanized at the end of the study for blood and tissue collection. HFD increased body mass and adiposity in both sexes. Chronic angiotensin-(1-7) infusion significantly decreased body mass and adiposity and increased lean mass in obese mice of both sexes. While both sexes tended to develop mild hyperglycemia in response to HFD, female mice developed less marked hyperinsulinemia. There was no effect of angiotensin-(1-7) on fasting glucose or insulin levels among diet and sex groups. Male and female mice similarly developed insulin resistance and glucose intolerance in response to HFD feeding. Angiotensin-(1-7) improved insulin sensitivity in both sexes but corrected glucose intolerance only in obese female mice. There were no effects of sex or angiotensin-(1-7) treatment on any of the study outcomes in control diet-fed mice. This study provides new evidence for sex differences in the impact of chronic angiotensin-(1-7) in obese mice, with females having greater changes in glucose tolerance with treatment. These findings improve understanding of sex differences in renin-angiotensin mechanisms in obesity and illustrate the potential for targeting angiotensin-(1-7) for treatment of this condition.