The loss of ERE-dependent ERα signaling potentiates the effects of maternal high-fat diet on energy homeostasis in female offspring fed an obesogenic diet.
The loss of ERE-dependent ERα signaling potentiates the effects of maternal high-fat diet on energy homeostasis in female offspring fed an obesogenic diet.
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ERE 依赖性 ERα 信号的丧失增强了母亲高脂肪饮食对肥胖饮食喂养的雌性后代能量稳态的影响。
DOI：
10.1017/s2040174419000515
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发表时间：
2020
影响因子：
1.7
通讯作者：
Mamounis,KyleJ
中科院分区：
文献类型：
--
作者：
Roepke,TroyA;Yasrebi,Ali;Villalobos,Alejandra;Krumm,ElizabethA;Yang,JenniferA;Mamounis,KyleJ
母亲的高脂肪饮食（HFD）会改变啮齿动物的下丘脑编程并破坏后代的能量稳态。我们之前报道过，ERα 信号传导的缺失部分阻断了母体 HFD 对喂养标准食物的雌性后代的影响。在一项配套研究中，我们确定了在转基因小鼠模型中，成年肥胖饮食是否会放大母体 HFD 的影响。杂合 ERα 敲除（野生型 (WT)/KO）母鼠在与杂合雄性（WT/KO 或 WT/敲除）交配前 4 周饲喂对照种鸡饲料（25% 脂肪）或半纯化 HFD（45% 脂肪），以产生 WT、ERα KO 或 ERα 敲除/敲除 (KIKO)（无雌激素反应元件） (ERE) 结合）雌性后代，喂食 HFD 20 周。由于肥胖增加和活动减少，母亲 HFD 增强了成人 HFD 对 KIKO 和 KO 体重的影响。母体 HFD 还产生了 KIKO 雌性，这些雌性表现出类似 KO 的胰岛素不耐受和葡萄糖稳态受损。母体 HFD 仅在 WT 小鼠中增加血浆白细胞介素 6 和单核细胞趋化蛋白 1 水平以及 G6pc 和 Pepck 肝脏表达。 HFD 喂养的 KO 后代的胰岛素和肿瘤坏死因子 α 水平较高。 Esr1 的弓形和肝脏表达在 KIKO 和 WT 中分别发生改变。这些数据表明，ERE 依赖性 ERα 信号传导的丧失，而不是全部 ERα 信号传导的丧失，使雌性对母体 HFD 可能通过控制外周炎症以及下丘脑和肝脏基因表达对后代能量和葡萄糖的有害影响敏感。未来的研究将通过 ERα 信号探究母体 HFD 编程的组织特异性机制。
Maternal high-fat diet (HFD) alters hypothalamic programming and disrupts offspring energy homeostasis in rodents. We previously reported that the loss of ERα signaling partially blocks the effects of maternal HFD in female offspring fed a standard chow diet. In a companion study, we determined if the effects of maternal HFD were magnified by an adult obesogenic diet in our transgenic mouse models. Heterozygous ERα knockout (wild-type (WT)/KO) dams were fed a control breeder chow diet (25% fat) or a semipurified HFD (45% fat) 4 weeks prior to mating with heterozygous males (WT/KO or WT/ knockin) to produce WT, ERα KO, or ERα knockin/knockout (KIKO) (no estrogen response element (ERE) binding) female offspring, which were fed HFD for 20 weeks. Maternal HFD potentiated the effects of adult HFD on KIKO and KO body weight due to increased adiposity and decreased activity. Maternal HFD also produced KIKO females that exhibit KO-like insulin intolerance and impaired glucose homeostasis. Maternal HFD increased plasma interleukin 6 and monocyte chemoattractant protein 1 levels and G6pc and Pepck liver expression only in WT mice. Insulin and tumor necrosis factor α levels were higher in KO offspring from HFD-fed dams. Arcuate and liver expression of Esr1 was altered in KIKO and WT, respectively. These data suggest that loss of ERE-dependent ERα signaling, and not total ERα signaling, sensitizes females to the deleterious influence of maternal HFD on offspring energy and glucose potentially through the control of peripheral inflammation and hypothalamic and liver gene expression. Future studies will interrogate the tissue-specific mechanisms of maternal HFD programming through ERα signaling.