PDF(Pubmed)
Abstract：
OBJECTIVE: Menopause adversely impacts systemic energy metabolism and increases the risk of metabolic disease(s) including hepatic steatosis, but the mechanisms are largely unknown. Dosing female mice with vinyl cyclohexene dioxide (VCD) selectively causes follicular atresia in ovaries, leading to a murine menopause-like phenotype.
METHODS: In this study, we treated female C57BL6/J mice with VCD (160 mg/kg i.p. for 20 consecutive days followed by verification of the lack of estrous cycling) to investigate changes in body composition, energy expenditure (EE), hepatic mitochondrial function, and hepatic steatosis across different dietary conditions.
RESULTS: VCD treatment induced ovarian follicular loss and increased follicle-stimulating hormone (FSH) levels in female mice, mimicking a menopause-like phenotype. VCD treatment did not affect body composition, or EE in mice on a low-fat diet (LFD) or in response to a short-term (1-week) high-fat, high sucrose diet (HFHS). However, the transition to a HFHS lowered cage activity in VCD mice. A chronic HFHS diet (16 weeks) significantly increased weight gain, fat mass, and hepatic steatosis in VCD-treated mice compared to HFHS-fed controls. In the liver, VCD mice showed suppressed hepatic mitochondrial respiration on LFD, while chronic HFHS resulted in compensatory increases in hepatic mitochondrial respiration. Also, liver RNA sequencing revealed that VCD promoted global upregulation of hepatic lipid/cholesterol synthesis pathways.
CONCLUSIONS: Our findings suggest that the VCD-induced menopause model compromises hepatic mitochondrial function and lipid/cholesterol homeostasis that sets the stage for HFHS diet-induced steatosis while also increasing susceptibility to obesity.
METHODS: In this study, we treated female C57BL6/J mice with VCD (160 mg/kg i.p. for 20 consecutive days followed by verification of the lack of estrous cycling) to investigate changes in body composition, energy expenditure (EE), hepatic mitochondrial function, and hepatic steatosis across different dietary conditions.
RESULTS: VCD treatment induced ovarian follicular loss and increased follicle-stimulating hormone (FSH) levels in female mice, mimicking a menopause-like phenotype. VCD treatment did not affect body composition, or EE in mice on a low-fat diet (LFD) or in response to a short-term (1-week) high-fat, high sucrose diet (HFHS). However, the transition to a HFHS lowered cage activity in VCD mice. A chronic HFHS diet (16 weeks) significantly increased weight gain, fat mass, and hepatic steatosis in VCD-treated mice compared to HFHS-fed controls. In the liver, VCD mice showed suppressed hepatic mitochondrial respiration on LFD, while chronic HFHS resulted in compensatory increases in hepatic mitochondrial respiration. Also, liver RNA sequencing revealed that VCD promoted global upregulation of hepatic lipid/cholesterol synthesis pathways.
CONCLUSIONS: Our findings suggest that the VCD-induced menopause model compromises hepatic mitochondrial function and lipid/cholesterol homeostasis that sets the stage for HFHS diet-induced steatosis while also increasing susceptibility to obesity.
摘要：
更年期对全身能量代谢产生不利影响，并增加代谢性疾病（包括肝脂肪变性）的风险，但机制在很大程度上是未知的。给雌性小鼠服用乙烯基环己烯二氧化（VCD）选择性地导致卵巢中的卵泡闭锁，导致鼠类更年期表型。在这项研究中,我们用VCD治疗雌性C57BL6/J小鼠（160mg/kg腹膜内连续20天，然后验证缺乏发情周期），以研究身体成分的变化，能量消耗(EE)，肝线粒体功能，不同饮食条件下的肝脂肪变性。VCD治疗导致雌性小鼠卵巢卵泡丢失和卵泡刺激素（FSH）水平增加，模仿更年期样表型。VCD治疗不影响身体成分，或EE的小鼠低脂饮食（LFD）或响应短期（1周）高脂肪，高蔗糖饮食（HFHS）。然而,向HFHS的过渡降低了VCD小鼠的笼子活动。慢性HFHS饮食（16周）显著增加体重增加，脂肪量,与HFHS喂养的对照相比，VCD处理的小鼠的肝脂肪变性。在肝脏中，VCD小鼠在LFD上显示肝脏线粒体呼吸受抑制，而慢性HFHS导致肝脏线粒体呼吸的代偿性增加。此外，肝脏RNA测序显示,VCD促进肝脏脂质/胆固醇合成途径的整体上调.我们的发现表明，VCD诱导的更年期模型损害了肝线粒体功能和脂质/胆固醇稳态，这为HFHS饮食诱导的脂肪变性奠定了基础，同时也增加了对肥胖的易感性。
