Abstract:
Although obesity and subsequent liver injury are increasingly prevalent in women, female mouse models have generally shown resistance to high-fat diet (HFD)-induced obesity. We evaluated control and HFD-fed male and female FVB/N mice, a strain well-suited to transgenic analyses, for phenotypic, histological, and molecular markers related to control of glucose, lipids, and inflammation in serum, liver, and perigonadal white adipose tissues. Unlike many mouse models, HFD-fed FVB/N females gained more perigonadal and mesenteric fat mass and overall body weight than their male counterparts, with increased hepatic expression of lipogenic PPARγ target genes (Cd36, Fsp27, and Fsp27β), oxidative stress genes and protein (Nqo1 and CYP2E1), inflammatory gene (Mip-2), and the pro-fibrotic gene Pai-1, along with increases in malondialdehyde and serum ALT levels. Further, inherent to females (independently of HFD), hepatic antioxidant heme oxygenase-1 (HMOX1, HO-1) protein levels were reduced compared to their male counterparts. In contrast, males may have been relatively protected from HFD-induced oxidative stress and liver injury by elevated mRNA and protein levels of hepatic antioxidants BHMT and Gpx2, increased fatty acid oxidation genes in liver and adipocytes (Pparδ), despite disorganized and inflamed adipocytes. Thus, female FVB/N mice offer a valuable preclinical, genetically malleable model that recapitulates many of the features of diet-induced obesity and liver damage observed in human females.
摘要:
尽管肥胖和随后的肝损伤在女性中越来越普遍,雌性小鼠模型通常显示出对高脂肪饮食(HFD)诱导的肥胖的抗性。我们评估了对照和HFD喂养的雄性和雌性FVB/N小鼠,一种非常适合转基因分析的菌株,对于表型,组织学,以及与葡萄糖控制相关的分子标记,脂质,和血清中的炎症,肝脏,和周围白色脂肪组织。与许多老鼠模型不同,HFD喂养的FVB/N雌性比雄性雌性获得了更多的外周和肠系膜脂肪量和整体体重,随着脂肪生成PPARγ靶基因(Cd36,Fsp27和Fsp27β)的肝表达增加,氧化应激基因和蛋白质(Nqo1和CYP2E1),炎症基因(Mip-2),和促纤维化基因Pai-1,以及丙二醛和血清ALT水平的增加。Further,女性固有的(独立于HFD),与男性相比,肝脏抗氧化剂血红素加氧酶-1(HMOX1,HO-1)蛋白水平降低。相比之下,通过肝脏抗氧化剂BHMT和Gpx2的mRNA和蛋白质水平升高,肝脏和脂肪细胞中脂肪酸氧化基因增加(Pparδ),男性可能已相对保护免受HFD诱导的氧化应激和肝损伤,尽管脂肪细胞混乱和发炎。因此,雌性FVB/N小鼠提供了有价值的临床前,遗传可塑性模型,概括了在人类女性中观察到的饮食诱导的肥胖和肝损伤的许多特征。