美国加州大学旧金山分校Holly A. Ingraham、冷泉港实验室Jessica Tollkuhn等研究人员合作发现，雌性激素调动大脑MC4R信号来驱动雌性小鼠的身体活动。这一研究成果于2021年10月13日在线发表在国际学术期刊《自然》上。

研究人员发现，腹内侧下丘脑的腹外侧亚核（VMHvl）的雌激素敏感神经元亚群投射到海马和后脑的唤醒中心，并使雌激素能够重新平衡雌性小鼠的能量分配。17β-雌二醇（E2）的激增通过直接招募雌激素受体α（ERα）到Mc4r基因来增加这些VMHvl神经元的黑色皮质素-4受体（MC4R）信号。在对同时表达MC4R和ERα的VMHvl神经元进行化学遗传刺激后，雌激素耗尽的雌性小鼠的静止行为和肥胖症被逆转。

同样，在CRISPR介导的该节点的激活后，身体活动的长期增加被观察到。这些数据将MC4R（单基因人类肥胖的最常见原因）信号的影响扩展到了调节食物摄入量之外，并合理地解释了黑色皮质素信号的性别差异，包括女性MC4R不足的更大疾病严重程度。这种激素依赖性节点阐明了生殖周期中的雌激素在激励行为和维持女性积极生活方式方面的功能。

据悉，雌激素在啮齿动物和人类中的耗竭导致不活动、脂肪堆积和糖尿病，强调了雌激素的保守代谢益处，而这种益处不可避免地随着年龄的增长而减少。在啮齿类动物中，排卵前E2的激增会暂时增加能量消耗，用于协调身体活动的增加和性接受能力的峰值。

附：英文原文

Title: Oestrogen engages brain MC4R signalling to drive physical activity in female mice

Author: Krause, William C., Rodriguez, Ruben, Gegenhuber, Bruno, Matharu, Navneet, Rodriguez, Andreas N., Padilla-Roger, Adriana M., Toma, Kenichi, Herber, Candice B., Correa, Stephanie M., Duan, Xin, Ahituv, Nadav, Tollkuhn, Jessica, Ingraham, Holly A.

Issue&Volume: 2021-10-13

Abstract: Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes1,2, 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.

DOI: 10.1038/s41586-021-04010-3

Source: https://www.nature.com/articles/s41586-021-04010-3