School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia.
J Biol Rhythms. 2018 Jun;33(3):289-301. doi: 10.1177/0748730418772499.
Obesity during pregnancy causes numerous maternal and fetal health complications, but the underlying mechanisms remain unclear. Adipose tissue dysfunction in obesity has previously been linked to disruption of the intrinsic adipose clock gene network that is crucial for normal metabolic function. This adipose clock also undergoes major change as part of the maternal metabolic adaptation to pregnancy, but whether this is affected by maternal obesity is unknown. Consequently, in this study we tested the hypothesis that obesity disturbs rhythmic gene expression in maternal adipose tissue across pregnancy. A rat model of maternal obesity was established by cafeteria (CAF) feeding, and adipose expression of clock genes and associated nuclear receptors ( Ppars and Pgc1α) was measured across days 15-16 and 21-22 of gestation (term = 23 days). CAF feeding suppressed the mesor and/or amplitude of adipose tissue clock genes (most notably Bmal1, Per2, and Rev-erbα) relative to chow-fed controls (CON) across both days of gestation. On day 15, the CAF diet also induced adipose Pparα, Pparδ, and Pgc1α rhythmicity but repressed that of Pparγ, while expression of Pparα, Pparδ, and Pgc1α was reduced at select time points. CAF mothers were hyperleptinemic at both stages of gestation, and at day 21 this effect was time-of-day dependent. Fetal plasma leptin exhibited clear rhythmicity, albeit with low amplitude, but interestingly these levels were unaffected by CAF feeding. Our data show that maternal obesity disrupts rhythmic expression of clock and metabolic genes in maternal adipose tissue and leads to maternal but not fetal hyperleptinemia.
孕期肥胖会导致许多母婴健康并发症，但其中的潜在机制尚不清楚。先前的研究表明，肥胖时脂肪组织功能障碍与内在脂肪时钟基因网络的破坏有关，而该网络对于正常的代谢功能至关重要。脂肪时钟也会随着母体代谢适应妊娠而发生重大变化，但母体肥胖是否会影响这一变化尚不清楚。因此，在这项研究中，我们检验了肥胖是否会扰乱母体脂肪组织在整个妊娠过程中的节律性基因表达这一假说。通过 cafeteria（CAF）喂养建立了母体肥胖大鼠模型，并在妊娠第 15-16 天和第 21-22 天（足月= 23 天）测量脂肪时钟基因和相关核受体（Ppars 和 Pgc1α）的表达。与对照（CON）相比，CAF 喂养在整个妊娠期间均抑制了脂肪组织时钟基因（尤其是 Bmal1、Per2 和 Rev-erbα）的中值和/或振幅。在第 15 天，CAF 饮食还诱导了脂肪组织中 Pparα、Pparδ 和 Pgc1α 的节律性表达，但抑制了 Pparγ 的节律性表达，而在某些时间点，Pparα、Pparδ 和 Pgc1α 的表达减少。CAF 母亲在妊娠的两个阶段均表现出高瘦素血症，而在第 21 天，这种影响具有时间依赖性。胎儿血浆瘦素表现出明显的节律性，尽管幅度较低，但有趣的是，CAF 喂养并没有影响其节律性。我们的数据表明，母体肥胖会扰乱母体脂肪组织中时钟和代谢基因的节律性表达，并导致母体而非胎儿的高瘦素血症。
