Data Sheet 3_Effects of voluntary wheel running on appetite-regulating peptides and neuroinflammation in the hypothalamus of ovariectomized middle-aged mice.docx

The postmenopausal period is associated with an increased tendency to gain weight. This may be due to disturbances in appetite regulation, mainly in the hypothalamus and nutritional behaviors, as well as persistent neuroinflammation resulting from estrogen deficiency. Research indicates that physical activity may counteract estrogen deficiency by improving hypothalamic regulation of appetite and inflammation, thereby promoting better energy balance and decreasing the risk of weight gain after menopause. We investigated whether voluntary wheel running (VWR) impacts factors related to appetite, energy homeostasis, and neuroinflammatory changes induced by ovariectomy (OVX). Thus, 13-month-old female mice underwent OVX, creating a comprehensive model of reproductive aging in females. Ovariectomized (OVX-VWR) and sham-operated (SHAM-VWR) mice were subjected to 6 weeks of VWR. The control sedentary groups (SHAM-SED, OVX-SED) were housed with immobilized wheels. The body mass, food and water intake, and daily running activity were recorded. Hypothalamic and serum samples were collected to examine the expression levels of genes, proteins, and hormones related to appetite regulation and neuroinflammation processes. OVX mice gained weight most excessively and showed reduced running activity. OVX downregulated the ERα/ERβ ratio, and VWR increased ERβ expression. VWR increased Lepr and Cckar expression in the sham-operated group. VWR has an impact on hypothalamic neuroinflammation regardless of ovarian status, through changes in expression of NLRP3, pro-IL-18, TLR4, pro-caspase 1, Il-1b, and Il-18. OVX in middle-aged mice altered body weight and energy metabolism, but did not affect food intake. VWR modulated hypothalamic appetite-regulating factors—changes not seen in OVX females—and elicited a comparable neuroinflammatory response in the hypothalamus of both SHAM- and OVX-operated mice.

绝经后期与体重增加风险升高显著相关。该现象的潜在机制包括食欲调节紊乱（主要累及下丘脑与营养行为），以及雌激素缺乏诱发的持续性神经炎症。研究显示，体育活动可通过改善下丘脑对食欲与炎症的调控，对抗雌激素缺乏状态，进而优化能量稳态，降低绝经后体重增加风险。本研究旨在探究自愿转轮运动（Voluntary Wheel Running, VWR）是否可影响卵巢摘除术（Ovariectomy, OVX）诱导的食欲调节、能量稳态及神经炎症变化相关因子。为此，研究人员对13月龄雌性小鼠实施卵巢摘除术，构建雌性生殖衰老的完整模型。将卵巢摘除+转轮运动组（OVX-VWR）与假手术+转轮运动组（SHAM-VWR）小鼠纳入为期6周的自愿转轮运动干预；静坐对照组（SHAM-SED、OVX-SED）则饲养于固定转轮装置中。研究人员记录了各组小鼠的体重、摄食量、饮水量以及每日转轮运动活动量，并收集下丘脑与血清样本，用以检测食欲调节及神经炎症通路相关基因、蛋白质与激素的表达水平。结果显示，卵巢摘除术组小鼠体重过度增加，且转轮运动活动量显著降低；卵巢摘除术会下调雌激素受体α/β（ERα/ERβ）的比值，而自愿转轮运动可上调ERβ的表达水平。自愿转轮运动可在假手术组小鼠中上调瘦素受体基因（Lepr）与胆囊收缩素A受体基因（Cckar）的表达水平。无论卵巢状态如何，自愿转轮运动均可通过改变NLRP3、前体IL-18、TLR4、前体半胱天冬酶1、Il-1b及Il-18的表达水平，调控下丘脑神经炎症进程。中年小鼠接受卵巢摘除术后，体重与能量代谢发生显著改变，但摄食量未受影响。自愿转轮运动可调控下丘脑食欲调节因子的表达（该变化在卵巢摘除术雌性小鼠中未出现），并在假手术组与卵巢摘除术组小鼠的下丘脑中引发相似的神经炎症反应。