Nag Sourashish, Khan Mohammad Azhar, Samuel Preethi, Ali Quaisar, Hussain Tahir
Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204.
Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204.
Metabolism. 2015 Jul;64(7):814-25. doi: 10.1016/j.metabol.2015.01.019. Epub 2015 Mar 14.
Obesity is a known risk factor for various metabolic disorders and cardiovascular diseases. Recently we demonstrated that female angiotensin AT2 receptor (AT2R) knockout mice on high-fat diet (HFD) had higher body weight and adiposity with a parallel reduction in estrogen (17,β-estradiol/E2). The present study investigated whether the anti-adiposity effects of the AT2R are estrogen-dependent in female mice.
Female C57BL/6 ovary-intact (Ovi) mice were treated with an AT2R agonist (C21, 0.3 mg/kg, daily i.p.). Ovariectomized (Ovx) mice, supplemented with E2 (5 μg/day, pellets implanted subcutaneously), were treated with an AT2R agonist (C21, 0.3 mg/kg, daily i.p.) or vehicle. After 4-days of pre-treatment with C21, Ovi and Ovx mice were placed on either normal diet (ND) or HFD while the C21 treatment continued for the next 10 days. For a long-term study, Ovi mice were placed on HFD and treated with C21 for 12 weeks.
Ovi mice fed the HFD had increased parametrial white adipose tissue (pWAT) weight, plasma free fatty acid and triglycerides compared to Ovi mice on ND. Ovariectomy alone caused similar changes in these parameters which were further increased by HFD-feeding. C21 treatment attenuated these HFD-induced changes in Ovi as well as Ovx mice. HFD also, increased the liver/body-weight ratio and decreased the liver expression of the β-oxidation enzyme, carnitine palmitoyltransferase 1 (CPT1-A). C21 treatment attenuated these changes as well. The long-term C21 treatment of Ovi mice lowered the HFD-induced body weight gain, increase in pWAT weight, parametrial adipocyte size and hyperinsulinemia induced by HFD. Finally, HFD drastically reduced urinary estrogen and the beneficial metabolic changes in response to C21-treatment occurred without significantly increasing urinary estrogen.
We suggest that the pharmacological activation of AT2R by the agonist C21 reduces adiposity and body weight gain independent of estrogen in female mice. Improvement in fatty acid metabolism is a potential mechanism by which the AT2R exerts anti-adiposity effects.
肥胖是多种代谢紊乱和心血管疾病的已知危险因素。最近我们证明，高脂饮食（HFD）喂养的雌性血管紧张素AT2受体（AT2R）基因敲除小鼠体重和肥胖程度更高，同时雌激素（17β-雌二醇/E2）水平降低。本研究调查了AT2R的抗肥胖作用在雌性小鼠中是否依赖雌激素。
对雌性C57BL/6完整卵巢（Ovi）小鼠腹腔注射AT2R激动剂（C21，0.3mg/kg，每日一次）。对卵巢切除（Ovx）小鼠皮下植入含E2（5μg/天）的微渗透泵，并腹腔注射AT2R激动剂（C21，0.3mg/kg，每日一次）或溶剂。用C21预处理4天后，将Ovi和Ovx小鼠置于正常饮食（ND）或HFD中，同时继续C21处理10天。在长期研究中，将Ovi小鼠置于HFD中，并用C21处理12周。
与喂食ND的Ovi小鼠相比，喂食HFD的Ovi小鼠子宫旁白色脂肪组织（pWAT）重量、血浆游离脂肪酸和甘油三酯增加。单独卵巢切除导致这些参数出现类似变化，而HFD喂养进一步加剧了这些变化。C21处理减轻了Ovi和Ovx小鼠中这些由HFD诱导的变化。HFD还增加了肝脏/体重比，并降低了肝脏中β-氧化酶肉碱棕榈酰转移酶1（CPT1-A）的表达。C21处理也减轻了这些变化。对Ovi小鼠进行长期C21处理可降低HFD诱导的体重增加、pWAT重量增加、子宫旁脂肪细胞大小增加以及HFD诱导的高胰岛素血症。最后，HFD显著降低了尿雌激素水平，并且在不显著增加尿雌激素的情况下，出现了对C21处理有益的代谢变化。
我们认为，激动剂C21对AT2R的药理激活可降低雌性小鼠的肥胖和体重增加，且不依赖雌激素。脂肪酸代谢的改善是AT2R发挥抗肥胖作用的潜在机制。
