BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

中文翻译：

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肥胖小鼠中血管紧张素-（1-7）处理的代谢效应中的性别差异。

背景技术血管紧张素-（1-7）是肾素-血管紧张素系统的有益激素，已知在调节血压和葡萄糖稳态中起积极作用。先前的研究表明，在高脂饮食（HFD）诱导的肥胖雄性小鼠中，循环血管紧张素（1-7）的水平降低，这种激素的长期恢复可逆转饮食诱导的胰岛素抵抗。然而，这尚未在雌性小鼠中进行检查。我们假设血管紧张素-（1-7）可以改善肥胖雌性小鼠的胰岛素敏感性和葡萄糖耐量，与先前在雄性小鼠中观察到的程度相似。方法将五周大的雄性和雌性C57BL / 6J小鼠（8-12只/组）置于对照饮食或HFD（分别来自脂肪的16％或59％大卡）中进行11周。饮食8周后，将小鼠植入渗透泵以皮下递送血管紧张素-（1-7）（400 ng / kg / min）或生理盐水载体3周。在治疗的最后一周，测量了体重和组成，并进行了腹膜内胰岛素和葡萄糖耐量测试，以分别评估胰岛素敏感性和葡萄糖耐量。在研究结束时对小鼠实施安乐死以收集血液和组织。结果HFD男女均增加体重和肥胖。慢性血管紧张素-（1-7）输注显着降低了男女肥胖小鼠的体重和肥胖，并增加了瘦体重。虽然两种性别都倾向于对HFD产生轻度高血糖症，但雌性小鼠的低胰岛素血症明显。在饮食和性别人群中，血管紧张素-（1-7）对空腹血糖或胰岛素水平没有影响。雄性和雌性小鼠响应HFD喂养而相似地出现胰岛素抵抗和葡萄糖不耐症。血管紧张素-（1-7）改善了男女的胰岛素敏感性，但仅在肥胖的雌性小鼠中纠正了葡萄糖耐受不良。在对照组饮食喂养的小鼠中，性别或血管紧张素-（1-7）治疗对任何研究结果均无影响。结论本研究为肥胖小鼠中慢性血管紧张素-（1-7）的影响中的性别差异提供了新证据，雌性在治疗中对葡萄糖耐量的变化更大。这些发现增进了对肥胖中肾素-血管紧张素机制中性别差异的理解，并说明了靶向血管紧张素-（1-7）治疗该病的潜力。血管紧张素-（1-7）改善了男女的胰岛素敏感性，但仅在肥胖的雌性小鼠中纠正了葡萄糖耐受不良。在对照组饮食喂养的小鼠中，性别或血管紧张素-（1-7）治疗对任何研究结果均无影响。结论本研究为肥胖小鼠中慢性血管紧张素-（1-7）的影响中的性别差异提供了新的证据，雌性在治疗中对葡萄糖耐量的变化更大。这些发现增进了对肥胖中肾素-血管紧张素机制中性别差异的理解，并说明了靶向血管紧张素-（1-7）治疗该病的潜力。血管紧张素-（1-7）改善了男女的胰岛素敏感性，但仅在肥胖的雌性小鼠中纠正了葡萄糖耐受不良。在对照组饮食喂养的小鼠中，性别或血管紧张素-（1-7）治疗对任何研究结果均无影响。结论本研究为肥胖小鼠中慢性血管紧张素-（1-7）的影响中的性别差异提供了新的证据，雌性在治疗中对葡萄糖耐量的变化更大。这些发现增进了对肥胖中肾素-血管紧张素机制中性别差异的理解，并说明了靶向血管紧张素-（1-7）治疗该病的潜力。结论本研究为肥胖小鼠中慢性血管紧张素-（1-7）的影响中的性别差异提供了新证据，雌性在治疗中对葡萄糖耐量的变化更大。这些发现增进了对肥胖中肾素-血管紧张素机制中性别差异的理解，并说明了靶向血管紧张素-（1-7）治疗该病的潜力。结论本研究为肥胖小鼠中慢性血管紧张素-（1-7）的影响中的性别差异提供了新证据，雌性在治疗中对葡萄糖耐量的变化更大。这些发现增进了对肥胖中肾素-血管紧张素机制中性别差异的理解，并说明了靶向血管紧张素-（1-7）治疗该病的潜力。