Human obesity has become a global health epidemic, with few safe and effective pharmacological therapies currently available. The systemic loss of ovarian estradiol (E2) in women after menopause greatly increases the risk of obesity and metabolic dysfunction, revealing the critical role of E2 in this setting. The salutary effects of E2 are traditionally attributed to the classical estrogen receptors ERα and ERβ, with the contribution of the G protein-coupled estrogen receptor (GPER) still largely unknown. Here, we used ovariectomy- and diet-induced obesity (DIO) mouse models to evaluate the preclinical activity of GPER-selective small-molecule agonist G-1 (also called Tespria) against obesity and metabolic dysfunction. G-1 treatment of ovariectomized female mice (a model of postmenopausal obesity) reduced body weight and improved glucose homeostasis without changes in food intake, fuel source usage, or locomotor activity. G-1-treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers but did not display feminizing effects on the uterus (imbibition) or beneficial effects on bone health. G-1 treatment of DIO male mice did not elicit weight loss but prevented further weight gain and improved glucose tolerance, indicating that G-1 improved glucose homeostasis independently of its antiobesity effects. However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, reflecting possible sex differences in the mechanisms of G-1 action. In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models.

中文翻译：

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GPER 选择性激动剂 G-1 在肥胖和糖尿病小鼠模型中的临床前疗效。

人类肥胖已成为全球健康流行病，目前几乎没有安全有效的药物疗法。绝经后女性卵巢雌二醇 (E2) 的全身性丢失大大增加了肥胖和代谢功能障碍的风险，揭示了 E2 在这种情况下的关键作用。E2 的有益作用传统上归因于经典的雌激素受体 ERα 和 ERβ，而 G 蛋白偶联雌激素受体 (GPER) 的贡献仍然很大程度上未知。在这里，我们使用卵巢切除术和饮食诱导的肥胖 (DIO) 小鼠模型来评估 GPER 选择性小分子激动剂 G-1（也称为 Tespria）对肥胖和代谢功能障碍的临床前活性。对切​​除卵巢的雌性小鼠（绝经后肥胖模型）进行 G-1 治疗可减轻体重并改善葡萄糖稳态，而不会改变食物摄入、燃料源使用或运动活动。G-1 治疗的雌性小鼠还表现出能量消耗增加、体脂含量降低、空腹胆固醇、葡萄糖、胰岛素和炎症标志物降低，但对子宫（吸水）或对骨骼健康没有有益影响。DIO 雄性小鼠的 G-1 治疗不会引起体重减轻，但会阻止体重进一步增加并改善葡萄糖耐量，这表明 G-1 改善了葡萄糖稳态，与其抗肥胖作用无关。然而，在去卵巢的 DIO 雌性小鼠中，G-1 继续引起体重减轻，这反映了 G-1 作用机制中可能存在的性别差异。综上所述，