State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China.
Department of Neuromuscular Disease, Children's Hospital of Fudan University, Shanghai, China.
EMBO Rep. 2022 Jul 5;23(7):e54132. doi: 10.15252/embr.202154132. Epub 2022 Jun 2.
Our knowledge of the coordination of intergenerational inheritance and offspring metabolic reprogramming by gastrointestinal endocrine factors is largely unknown. Here, we showed that secretin (SCT), a brain-gut peptide, is downregulated by overnutrition in pregnant mice and women. More importantly, genetic loss of SCT in the maternal gut results in undesirable phenotypes developed in offspring including enhanced high-fat diet (HFD)-induced obesity and attenuated browning of inguinal white adipose tissue (iWAT). Mechanistically, loss of maternal SCT represses iWAT browning in offspring by a global change in genome methylation pattern through upregulation of DNMT1. SCT functions to facilitate ubiquitination and degradation of DNMT1 by activating AMPKα, which contributes to the observed alteration of DNMT1 in progeny. Lastly, we showed that SCT treatment during pregnancy can reduce the development of obesity and improve glucose tolerance and insulin resistance in offspring of HFD-fed females, suggesting that SCT may serve as a novel biomarker or a strategy for preventing metabolic diseases.
我们对胃肠道内分泌因素协调代际遗传和后代代谢重编程的了解还很有限。在这里，我们发现脑肠肽分泌素（SCT）在肥胖的孕鼠和孕妇中表达下调。更重要的是，母源肠道中 SCT 的基因缺失会导致后代出现不良表型，包括增强高脂饮食（HFD）诱导的肥胖和减弱腹股沟白色脂肪组织（iWAT）的棕色化。在机制上，母源 SCT 的缺失通过全基因组甲基化模式的全局性改变，抑制 iWAT 棕色化，这种改变是通过上调 DNMT1 实现的。SCT 通过激活 AMPKα 来促进 DNMT1 的泛素化和降解，从而导致 DNMT1 在后代中的改变。最后，我们发现孕期 SCT 处理可以减少肥胖的发生，并改善 HFD 喂养雌性后代的葡萄糖耐量和胰岛素抵抗，这表明 SCT 可能作为一种新的生物标志物或预防代谢性疾病的策略。
