Visceral obesity in murine pregnancy

Maternal obesity is linked with increased adverse outcomes for mother and fetus. However, the metabolic impact of excessive fat accumulation within the altered hormonal context of pregnancy is not well understood. We used a murine model of obesity, the high fat diet-fed C57BL/6J mouse to determine adipose tissue-mediated molecular mechanisms driving metabolic dysfunction throughout pregnancy. Remarkably, obese mice exhibited a normalization of visceral fat accumulation at late-stage pregnancy (-53%, P<0.001 E18.5) to achieve levels comparable in mass (per gram of body weight) to that of non pregnant, control diet fed mice. Moreover, whilst obese pregnant mice showed a marked glucose intolerance and apparent insulin resistance at mid-stage pregnancy (E14.5), glucose homeostasis converged with that of lean pregnant mice at late-stage pregnancy, suggesting an unexpected amelioration of the worsening metabolic dysfunction in obese pregnant mice. Transcriptomic analysis of the late-stage visceral fat indicated reduced de novo lipogenic drive (Me1, Fasn, Scd1, Dgat2), retinol metabolism (Rdh11, Rbp4) and inflammation (Mcp1, Tnfalpha) in obese pregnant mice that was confirmed functionally by their lower adipose proinflammatory macrophage density. Elevated expression of estrogen receptor a (ERalpha) in visceral adipose tissue was identified as potential unifying mechanism for the transcriptional changes and reduced adiposity of late stage obese pregnancy. Support for a role for ERalpha was provided by experiments showing that the ERalpha selective agonist PPT suppressed lipogenesis in primary mouse adipocytes and suppressed Me1, Fasn, SCD1 and Dgat2 mRNA levels in mature female human ChubS7 clonal fat cells. Our data reveal a novel role for elevated visceral adipocyte estrogen signaling as a protective mechanism against visceral fat hypertrophy and inflammation in late pregnancy. Pregnant high fat, pregnant control fat, non pregnant high fat, non pregnant control fat. Five biologial replictes each (20 samples).母体肥胖与母亲及胎儿的不良妊娠结局风险升高密切相关。然而，在妊娠期间激素环境改变的背景下，脂肪过度堆积所产生的代谢影响尚未得到充分阐明。本研究采用肥胖小鼠模型——高脂饮食喂养的C57BL/6J小鼠——旨在明确贯穿整个妊娠过程的、由脂肪组织介导的代谢功能障碍分子机制。值得注意的是，妊娠晚期的肥胖小鼠内脏脂肪堆积量出现了显著恢复（下降53%，P<0.001，E18.5），其每克体重的脂肪质量可与未妊娠、普通饮食喂养的对照组小鼠相当。此外，尽管肥胖妊娠小鼠在妊娠中期（E14.5）表现出明显的葡萄糖耐量受损（glucose intolerance）与胰岛素抵抗（insulin resistance），但在妊娠晚期其血糖稳态（glucose homeostasis）已与瘦体型妊娠小鼠趋于一致，这表明肥胖妊娠小鼠的代谢功能障碍恶化情况出现了出人意料的改善。对妊娠晚期内脏脂肪的转录组学分析（Transcriptomic analysis）显示，肥胖妊娠小鼠的从头脂肪生成（de novo lipogenesis）驱动通路（Me1、Fasn、Scd1、Dgat2）、视黄醇代谢（retinol metabolism）通路（Rdh11、Rbp4）以及炎症通路（Mcp1、Tnfalpha）均出现下调，这一结果通过其更低的脂肪组织促炎巨噬细胞（proinflammatory macrophage）密度得到了功能层面的验证。我们发现内脏脂肪组织中雌激素受体α（ERα, estrogen receptor α）的表达升高，可能是导致肥胖妊娠晚期转录组改变与脂肪量减少的统一潜在机制。后续实验进一步验证了ERα的作用：雌激素受体α选择性激动剂（ERalpha selective agonist）PPT可抑制原代小鼠脂肪细胞的脂肪生成，并下调成熟女性源ChubS7克隆脂肪细胞中Me1、Fasn、SCD1及Dgat2的mRNA水平。本研究揭示了内脏脂肪细胞雌激素信号升高作为一种保护机制，可在妊娠晚期对抗内脏脂肪肥大与炎症反应。本数据集包含四组样本：高脂饮食妊娠组脂肪、普通饮食妊娠组脂肪、高脂饮食未妊娠组脂肪、普通饮食未妊娠组脂肪，每组均设置5次生物学重复，总计20个样本。