High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring.
High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring.
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DOI：
10.1371/journal.pone.0084209
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Shankar K
中科院分区：
文献类型：
--
作者：
Borengasser SJ;Kang P;Faske J;Gomez-Acevedo H;Blackburn ML;Badger TM;Shankar K
成年期肥胖的风险取决于从受孕开始就制定的计划。在动物模型中，暴露于母亲肥胖和高脂肪饮食会影响后代肥胖的风险。在其他长期变化中，肥胖大鼠的后代在断奶时出现高胰岛素血症、肝脏脂肪变性和肝脏脂肪生成基因表达。然而，导致后代代谢失调的确切潜在机制尚不清楚。使用过度喂养引起的肥胖大鼠模型，我们之前证明，从孕前到出生暴露于母亲肥胖，足以增加后代的肥胖风险。肥胖鼠坝的后代在饲喂高脂肪饲料（HFD）时，体重和脂肪量均高于瘦鼠坝。由于昼夜节律的破坏已知会对肝脏等代谢活跃组织产生不利影响，因此我们研究了母体肥胖导致核心时钟成分扰乱从而导致后代肝脏能量代谢的假设。在短时间（2周）的HFD刺激后，在出生后第35天对瘦鼠和肥胖鼠的后代进行检查。在暴露于母亲肥胖和HFD的后代中，肝脏昼夜节律（CLOCK, BMAL1, rev - erba α， CRY， PER）和代谢（PPARα, SIRT1）基因的mRNA表达被强烈抑制。利用数学模型，我们确定了两种不同的调节PPARα mRNA表达的生物学机制：1)降低mRNA合成速率；ii)非特异性mRNA降解率增加。此外，我们的研究结果表明，PPARα转录的变化与PPARα转录起始位点附近H3K4me3和H3K27me3组蛋白标记的表观基因组改变有关。我们的研究结果表明，肥胖大鼠的后代对昼夜节律机制有不利的改变，这可能导致肝脏代谢受损，以应对HFD，特别是通过在肥胖发生之前减少PPARα表达。
The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosis, and lipogenic gene expression in the liver at weaning. However, the precise underlying mechanisms leading to metabolic dysregulation in the offspring remains unclear. Using a rat model of overfeeding-induced obesity, we previously demonstrated that exposure to maternal obesity from pre-conception to birth, is sufficient to program increased obesity risk in the offspring. Offspring of obese rat dams gain greater body weight and fat mass when fed high fat diet (HFD) as compared to lean dam. Since, disruptions of diurnal circadian rhythm are known to detrimentally impact metabolically active tissues such as liver, we examined the hypothesis that maternal obesity leads to perturbations of core clock components and thus energy metabolism in offspring liver. Offspring from lean and obese dams were examined at post-natal day 35, following a short (2 wk) HFD challenge. Hepatic mRNA expression of circadian (CLOCK, BMAL1, REV-ERBα, CRY, PER) and metabolic (PPARα, SIRT1) genes were strongly suppressed in offspring exposed to both maternal obesity and HFD. Using a mathematical model, we identified two distinct biological mechanisms that modulate PPARα mRNA expression: i) decreased mRNA synthesis rates; and ii) increased non-specific mRNA degradation rate. Moreover, our findings demonstrate that changes in PPARα transcription were associated with epigenomic alterations in H3K4me3 and H3K27me3 histone marks near the PPARα transcription start site. Our findings indicated that offspring from obese rat dams have detrimental alternations to circadian machinery that may contribute to impaired liver metabolism in response to HFD, specifically via reduced PPARα expression prior to obesity development.
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影响因子：
4.8
作者：
Etchegaray, Jean-Pierre;Yang, Xiaoming;Reppert, Steven M.
通讯作者：
Reppert, Steven M.
昼夜节律的代谢和能量学的融合。
DOI：
10.1126/science.1195027
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bass J;Takahashi JS
通讯作者：
Takahashi JS
影响因子：
3.7
作者：
Borengasser SJ;Lau F;Kang P;Blackburn ML;Ronis MJ;Badger TM;Shankar K
通讯作者：
Shankar K
影响因子：
4.8
作者：
Borengasser, Sarah J.;Zhong, Ying;Shankar, Kartik
通讯作者：
Shankar, Kartik
影响因子：
16
作者：
Feng, Dan;Lazar, Mitchell A.
通讯作者：
Lazar, Mitchell A.