Department of Anatomy, University of Otago, Dunedin, New Zealand.
Centre for Neuroendocrinology, University of Otago, Dunedin, New Zealand.
Geroscience. 2024 Dec;46(6):6127-6140. doi: 10.1007/s11357-024-01192-2. Epub 2024 May 22.
17α-Estradiol (17αE2), a less-feminising enantiomer of 17β-estradiol, has been shown to prolong lifespan and improve metabolic health in a sex-specific manner in male, but not in female mice. Recent studies have demonstrated the pivotal role of estrogen receptor α (ERα) in mediating the effects of 17αE2 on metabolic health. However, the specific tissues and/or neuronal signalling pathways that 17αE2 acts through remain to be elucidated. ERα expression in glutamatergic and GABAergic neurons (principal excitatory and inhibitory neurons respectively) in the hypothalamus is essential for estradiol signalling. Therefore, we hypothesised that knocking out ERα from one of these neuronal populations would attenuate the established beneficial metabolic effects of 17αE2 in male mice exposed to a high fat diet. To test this hypothesis we used two established brain specific ERα KO models, targeting either glutamatergic or GABAergic neurons (Vglut2/Vgat-ERαKO). We show that both of these ERα KO models exhibit a strong reduction in ERα expression in the arcuate nucleus of the hypothalamus, a control centre for metabolic regulation. Deletion of ERα from GABAergic neurons significantly diminished the effect of 17αE2 on body weight relative to controls, although these animals still show metabolic benefits with 17αE2 treatment. The response to 17αE2 was unaffected by ERα deletion in glutamatergic neurons. Our results support a benefit of 17αE2 treatment in protection against metabolic dysfunction, but these effects do not depend on exclusive ERα expression in glutamatergic and GABAergic neurons and persist when ERα expression is strongly reduced in the arcuate nucleus of the hypothalamus.
17α-雌二醇（17αE2）是 17β-雌二醇的非雌性化对映体，已被证明以性别特异性的方式延长雄性而非雌性小鼠的寿命并改善代谢健康。最近的研究表明，雌激素受体α（ERα）在介导 17αE2 对代谢健康的影响方面起着关键作用。然而，17αE2 作用的特定组织和/或神经元信号通路仍有待阐明。下丘脑谷氨酸能和 GABA 能神经元（分别为主要兴奋性和抑制性神经元）中 ERα 的表达对于雌二醇信号传导至关重要。因此，我们假设从这些神经元群体之一中敲除 ERα，会削弱暴露于高脂肪饮食的雄性小鼠中 17αE2 已建立的有益代谢作用。为了验证这一假设，我们使用了两种已建立的大脑特异性 ERα KO 模型，分别针对谷氨酸能或 GABA 能神经元（Vglut2/Vgat-ERαKO）。我们表明，这两种 ERα KO 模型均在下丘脑弓状核中表现出 ERα 表达的强烈减少，这是代谢调节的控制中心。从 GABA 能神经元中删除 ERα 会显著降低 17αE2 对体重的影响，相对于对照动物，但这些动物在接受 17αE2 治疗时仍表现出代谢益处。17αE2 的反应不受谷氨酸能神经元中 ERα 缺失的影响。我们的结果支持 17αE2 治疗在保护代谢功能障碍方面的益处，但这些影响不依赖于谷氨酸能和 GABA 能神经元中 ERα 的特异性表达，并且当下丘脑弓状核中 ERα 表达强烈减少时，这种作用仍然存在。
