Childhood obesity is a strong risk factor for adult obesity, type 2 diabetes, and cardiovascular disease. The mechanisms that link early adiposity with late-onset chronic diseases are poorly characterised. We developed a mouse model of early adiposity through litter size reduction. Mice reared in small litters (SLs) developed obesity, insulin resistance, and hepatic steatosis during adulthood. The liver played a major role in the development of the disease.

Objective

To gain insight into the molecular mechanisms that link early development and childhood obesity with adult hepatic steatosis and insulin resistance.

Methods

We analysed the hepatic transcriptome (Affymetrix) of control and SL mice to uncover potential pathways involved in the long-term programming of disease in our model.

Results

The circadian rhythm was the most significantly deregulated Gene Ontology term in the liver of adult SL mice. Several core clock genes, such as period 1–3 and cryptochrome 1–2, were altered in two-week-old SL mice and remained altered throughout their life course until they reached 4–6 months of age. Defective circadian rhythm was restricted to the periphery since the expression of clock genes in the hypothalamus, the central pacemaker, was normal. The period-cryptochrome genes were primarily entrained by dietary signals. Hence, restricting food availability during the light cycle only uncoupled the central rhythm from the peripheral and completely normalised hepatic triglyceride content in adult SL mice. This effect was accompanied by better re-alignment of the hepatic period genes, suggesting that they might have played a causal role in mediating hepatic steatosis in the adult SL mice. Functional downregulation of Per2 in hepatocytes in vitro confirmed that the period genes regulated lipid-related genes in part through peroxisome proliferator-activated receptor alpha (Ppara).

Conclusions

The hepatic circadian rhythm matures during early development, from birth to postnatal day 30. Hence, nutritional challenges during early life may misalign the hepatic circadian rhythm and secondarily lead to metabolic derangements. Specific time-restricted feeding interventions improve metabolic health in the context of childhood obesity by partially re-aligning the peripheral circadian rhythm.

中文翻译：

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哺乳期新生儿过度喂养会迅速且永久性地使肝脏昼夜节律失准并导致成人 NAFLD

儿童肥胖是成人肥胖、2 型糖尿病和心血管疾病的重要危险因素。将早期肥胖与迟发性慢性疾病联系起来的机制尚不清楚。我们通过减少窝产仔数开发了一种早期肥胖的小鼠模型。小窝 (SL) 饲养的小鼠在成年期会出现肥胖、胰岛素抵抗和肝脂肪变性。肝脏在疾病的发展中发挥了重要作用。

客观的

深入了解将早期发育和儿童肥胖与成人肝脂肪变性和胰岛素抵抗联系起来的分子机制。

方法

我们分析了对照和 SL 小鼠的肝脏转录组 (Affymetrix)，以揭示我们模型中与疾病长期编程有关的潜在途径。

结果

昼夜节律是成年 SL 小鼠肝脏中最显着失调的基因本体术语。几个核心时钟基因，例如周期 1-3和隐花色素 1-2, 在两周大的 SL 小鼠中发生了变化，并且在它们的整个生命过程中都保持着变化，直到它们达到 4-6 个月大。有缺陷的昼夜节律仅限于外周，因为下丘脑（中央起搏器）中的时钟基因表达正常。周期隐色素基因主要由饮食信号携带。因此，在光照循环期间限制食物供应只会使成年 SL 小鼠的中枢节律与外周和完全正常化的肝脏甘油三酯含量脱钩。这种效应伴随着肝周期基因的更好重新排列，表明它们可能在调节成年 SL 小鼠的肝脂肪变性中发挥了因果作用。Per2 的功能性下调在体外肝细胞中证实，周期基因部分通过过氧化物酶体增殖物激活受体α（Ppara）调节脂质相关基因。

结论

肝昼夜节律在早期发育过程中成熟，从出生到出生后第 30 天。因此，生命早期的营养挑战可能会使肝昼夜节律错位，继而导致代谢紊乱。在儿童肥胖的背景下，特定的限时喂养干预通过部分重新调整外周昼夜节律来改善代谢健康。