Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes^1,2, underscoring the conserved metabolic benefits of oestrogen that inevitably decrease with age. In rodents, the preovulatory surge in 17β-oestradiol (E2) temporarily increases energy expenditure to coordinate increased physical activity with peak sexual receptivity. Here we report that a subset of oestrogen-sensitive neurons in the ventrolateral ventromedial hypothalamic nucleus (VMHvl)^3,4,5,6,7 projects to arousal centres in the hippocampus and hindbrain, and enables oestrogen to rebalance energy allocation in female mice. Surges in E2 increase melanocortin-4 receptor (MC4R) signalling in these VMHvl neurons by directly recruiting oestrogen receptor-α (ERα) to the Mc4r gene. Sedentary behaviour and obesity in oestrogen-depleted female mice were reversed after chemogenetic stimulation of VMHvl neurons expressing both MC4R and ERα. Similarly, a long-term increase in physical activity is observed after CRISPR-mediated activation of this node. These data extend the effect of MC4R signalling — the most common cause of monogenic human obesity⁸ — beyond the regulation of food intake and rationalize reported sex differences in melanocortin signalling, including greater disease severity of MC4R insufficiency in women⁹. This hormone-dependent node illuminates the power of oestrogen during the reproductive cycle in motivating behaviour and maintaining an active lifestyle in women.

啮齿动物和人类的雌激素耗竭会导致缺乏活动、脂肪堆积和糖尿病^1,2，这强调了雌激素的保守代谢益处不可避免地会随着年龄的增长而降低。在啮齿类动物中，排卵前 17β-雌二醇 (E2) 的激增会暂时增加能量消耗，以协调体力活动的增加和性接受能力的峰值。在这里，我们报告了下丘脑腹外侧腹内侧核 (VMHvl) ^{3、4、5、6、7}中的一部分雌激素敏感神经元投射到海马体和后脑的觉醒中心，并使雌激素能够重新平衡雌性小鼠的能量分配。E2 的激增通过直接将雌激素受体-α (ERα) 招募到 Mc4r 来增加这些 VMHvl 神经元中的黑皮质素-4 受体 (MC4R)信号基因。在表达 MC4R 和 ERα 的 VMHvl 神经元的化学遗传学刺激后，雌激素耗尽的雌性小鼠的久坐行为和肥胖得到逆转。同样，在 CRISPR 介导的该节点激活后，观察到身体活动的长期增加。这些数据扩展了 MC4R 信号的影响——单基因人类肥胖的最常见原因⁸ ——超出了食物摄入的调节，并合理化了黑皮质素信号中报告的性别差异，包括女性 MC4R 功能不全的疾病严重程度⁹。这种激素依赖性节点阐明了雌激素在生殖周期中激发女性行为和维持积极生活方式的力量。