Effect of maternal obesity on estrous cyclicity, embryo development and blastocyst gene expression in a mouse model
Effect of maternal obesity on estrous cyclicity, embryo development and blastocyst gene expression in a mouse model
复制标题
DOI：
10.1093/humrep/des327
复制
发表时间：
2012-12-01
影响因子：
6.1
通讯作者：
Roberts, R. Michael
中科院分区：
文献类型：
--
作者：
Bermejo-Alvarez, Pablo;Rosenfeld, Cheryl S.;Roberts, R. Michael
研究问题：母体肥胖是否影响小鼠的动情周期、胚胎发育和囊胚基因表达？摘要回答：母体肥胖改变了动情周期，并导致两种关键代谢产物受体(SLC2A1和Ldlr)在从饮食诱导的肥胖女性中恢复的囊胚中下调，但胚胎发育不受影响。已知：母体肥胖由于围孕期的影响而降低生育力，但其负面影响是发情周期、卵母细胞质量或胚胎发育。STUDY设计、大小和持续时间：这是一项基于肥胖小鼠模型的随机研究。选用21只近交系NIH瑞士小鼠，在饲养前给予高脂饮食12周，以控制雄性肥胖。材料、环境和方法：雌性小鼠被喂养12周，然后与有生育能力的雄性小鼠共同居住。连续20天不能繁殖的小鼠被认为是不育的。对照组和饮食诱导的肥胖雌性在交配后3.5天被安乐死，采血进行血糖和激素测量，黄体计数和胚胎回收；通过qPCR.MAIN结果和机会的作用：5只Dio雌性无法繁殖并显示无排卵性卵巢(DiOI)，而其他7只Dio雌性(Diof)可以繁殖，尽管与对照组相比延长了一段时间。DIOF的体重明显小于DIOI。与C组相比，两组的血清胰岛素水平均升高，但血糖水平仅在不孕不育的DiOI组显著高于对照组。DiOI和DiOI小鼠体内脂联素水平均低于C组，瘦素水平高于C组。DiOF小鼠排卵的卵母细胞数与C组相同，胚胎发育到囊胚率正常。编码代谢激素受体(Insr、Igf1r、Igf2r、AdipoR1、AdipoR2和Lepr)和关键代谢酶(GAPDH、CPT1a和Sod2)的基因在DIOF和C囊胚中的表达没有差异，但代谢物受体(SLC2A1和LdR)的表达在DIOF中下调。为了限制偶然性的作用，实验在特定的实验室环境中进行，并有适当的对照组，动物被随机分配到每个实验组。此外，选择0.05的P值来确定两组之间观察到的差异是否具有统计学意义。限制和谨慎的理由：所获得的结果可能不能完全外推到人类。此外，由于在繁殖过程中没有监测卵泡活动，因此Diof组繁殖期延长的原因可能是正常周期动物发生的行为异常。研究结果的广泛意义：Dio改变了小鼠模型的发情周期，并证明了肥胖在不孕症中的作用。数据还表明，在远缘繁殖、遗传多样性的人群中，例如人类，个体对肥胖和与饮食相关的不孕不育的易感性存在。在有生育能力的肥胖女性身上观察到的囊胚发育似乎是正常的，这表明植入前的胚胎可以抵抗体内条件下脂肪酸和葡萄糖供应过剩造成的潜在不利后果。这种代谢的可塑性可能部分归因于下调代谢物转运体的能力，从而防止过度摄取营养。
STUDY QUESTION: Does maternal obesity affect estrous cyclicity, embryo development and blastocyst gene expression in mice?SUMMARY ANSWER: Maternal obesity alters estrous cyclicity and causes the down-regulation of two key metabolite receptors (Slc2a1 and Ldlr) in blastocysts recovered from diet-induced obese females, but embryo development is not affected.WHAT IS KNOWN ALREADY: Maternal obesity reduces fertility because of effects in the periconception period, but its negative influence is on estrous cyclicity, oocyte quality or embryo development.STUDY DESIGN, SIZE AND DURATION: This was a randomized study based on a mouse model for obesity. Twenty-one outbred NIH Swiss mice were used and obesity was induced by a diet high in fat administered for 12 weeks prior to breeding to control males.MATERIAL, SETTING AND METHODS: Females were fed either a control diet (C, n 9) or a diet high in fat [diet-induced obesity (DiO), n 12] for 12 weeks, and were then co-housed with fertile males. Mice that failed to breed during 20 consecutive days were considered infertile. Control and diet-induced obese females that demonstrated vaginal plugs were euthanized 3.5 days after mating, blood was sampled for glucose and hormone measurements, corpora lutea counted and embryos recovered; the relative mRNA abundance of 11 candidate genes was determined in blastocysts by qPCR.MAIN RESULTS AND THE ROLE OF CHANCE: Five DiO females failed to breed and displayed anovulatory ovaries (DiOI), whereas the other seven DiO females (DiOF) could breed, albeit over an extended period compared with controls. DiOF weighed significantly less than DiOI. Both groups had elevated serum insulin compared with C, although blood glucose level was only significantly higher than that in controls in the infertile DiOI group. Adiponectin was lower in the DiOI and leptin higher in both the DiOI and DiOF mice than in C. DiOF ovulated the same number of oocytes as C, and embryo development to blastocyst was normal. The expression of genes encoding metabolic hormone receptors (Insr, Igf1r, Igf2r, Adipor1, Adipor2 and Lepr) and key metabolic enzymes (Gapdh, Cpt1a and Sod2) did not differ between DiOF and C blastocysts, but that of metabolite receptors (Slc2a1 and Ldr) was down-regulated in DiOF. To limit the role of chance, the experiments were conducted in a defined laboratory setting with the proper controls, and the animals were randomly assigned to each experimental group. Moreover, a P-value of 0.05 was chosen to determine whether the differences observed between the groups were statistically significant.LIMITATIONS AND REASONS FOR CAUTION: The results obtained may not fully extrapolate to humans. Also, as follicular activity was not monitored while breeding, so the extended breeding period for DiOF group might be explained by behavioral abnormalities occurring in normal cycling animals.WIDER IMPLICATIONS OF THE FINDINGS: DiO alters the estrous cycle in the mouse model and demonstrates a role of obesity in infertility. The data also suggest that in an outbred, genetically diverse population, such as the human, individual susceptibility to obesity and associated infertility induced by diet exists. The apparently normal development to blastocyst observed in fertile, obese females suggests that preimplantation embryos can resist potentially adverse outcomes caused by an oversupply of fatty acids and glucose under in vivo conditions. This metabolic plasticity may, in part, be due to an ability to down-regulate metabolite transporters, thereby preventing excessive nutrient uptake.