Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
New Jersey Institute for Food, Nutrition, and Health, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
Sci Rep. 2017 Jul 25;7(1):6381. doi: 10.1038/s41598-017-06560-x.
Maternal high-fat diet (HFD) alters hypothalamic developmental programming and disrupts offspring energy homeostasis in rodents. 17β-estradiol (E2) also influences hypothalamic programming through estrogen receptor (ER) α. Therefore, we hypothesized that females lacking ERα would be more susceptible to maternal HFD. To address this question, heterozygous ERα knockout (WT/KO) dams were fed a control breeder chow diet (25% fat) or a semi-purified HFD (45% fat) 4 weeks prior to mating with WT/KO males or heterozygous males with an ERα DNA-binding domain mutation knocked in (WT/KI) to produce WT, ERα KO, or ERα KIKO females lacking ERE-dependent ERα signaling. Maternal HFD increased body weight in WT and KIKO, in part, due to increased adiposity and daytime carbohydrate utilization in WT and KIKO, while increasing nighttime fat utilization in KO. Maternal HFD also increased plasma leptin, IL-6, and MCP-1 in WT and increased arcuate expression of Kiss1 and Esr1 (ERα) and liver expression of G6pc and Pepck in WT and KIKO. Contrary to our hypothesis, these data suggest that loss of ERα signaling blocks the influence of maternal HFD on energy homeostasis, inflammation, and hypothalamic and liver gene expression and that restoration of ERE-independent ERα signaling partially reestablishes susceptibility to maternal HFD.
母体高脂肪饮食（HFD）改变了下丘脑的发育编程，并破坏了啮齿动物后代的能量稳态。17β-雌二醇（E2）也通过雌激素受体（ER）α影响下丘脑编程。因此，我们假设缺乏 ERα 的雌性对母体 HFD 更敏感。为了解决这个问题，杂合 ERα 敲除（WT/KO）母鼠在与 WT/KO 雄性或带有 ERα DNA 结合域突变的杂合雄性交配前 4 周接受对照繁殖者饲料（25%脂肪）或半纯化 HFD（45%脂肪）喂养，以产生缺乏 ERE 依赖性 ERα 信号的 WT、ERα KO 或 ERα KIKO 雌性。母体 HFD 增加了 WT 和 KIKO 的体重，部分原因是 WT 和 KIKO 的脂肪增加和白天碳水化合物利用率增加，而 KO 的夜间脂肪利用率增加。母体 HFD 还增加了 WT 和 KIKO 的血浆瘦素、IL-6 和 MCP-1，并增加了 WT 和 KIKO 的弓状表达 Kiss1 和 Esr1（ERα）以及肝脏表达 G6pc 和 Pepck。与我们的假设相反，这些数据表明，ERα 信号的丧失阻止了母体 HFD 对能量稳态、炎症以及下丘脑和肝脏基因表达的影响，而 ERE 非依赖性 ERα 信号的恢复部分重新建立了对母体 HFD 的易感性。
