Ramon-Krauel Marta, Pentinat Thais, Bloks Vincent W, Cebrià Judith, Ribo Silvia, Pérez-Wienese Ricky, Vilà Maria, Palacios-Marin Ivonne, Fernández-Pérez Antonio, Vallejo Mario, Téllez Noèlia, Rodríguez Miguel Àngel, Yanes Oscar, Lerin Carles, Díaz Rubén, Plosch Torsten, Tietge Uwe J F, Jimenez-Chillaron Josep C
Endocrinology Department, Institut de Recerca Sant Joan de Déu, Esplugues, Barcelona, Spain.
Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
FASEB J. 2018 May 29:fj201700717RR. doi: 10.1096/fj.201700717RR.
Postnatal overfeeding increases the risk of chronic diseases later in life, including obesity, insulin resistance, hepatic steatosis, and type 2 diabetes. Epigenetic mechanisms might underlie the long-lasting effects associated with early nutrition. Here we aimed to explore the molecular pathways involved in early development of insulin resistance and hepatic steatosis, and we examined the potential contribution of DNA methylation and histone modifications to long-term programming of metabolic disease. We used a well-characterized mouse model of neonatal overfeeding and early adiposity by litter size reduction. Neonatal overfeeding led to hepatic insulin resistance very early in life that persisted throughout adulthood despite normalizing food intake. Up-regulation of monoacylglycerol O-acyltransferase ( Mogat) 1 conceivably mediates hepatic steatosis and insulin resistance through increasing intracellular diacylglycerol content. Early and sustained deregulation of Mogat1 was associated with a combination of histone modifications that might favor Mogat1 expression. In sum, postnatal overfeeding causes extremely rapid derangements of hepatic insulin sensitivity that remain relatively stable until adulthood. Epigenetic mechanisms, particularly histone modifications, could contribute to such long-lasting effects. Our data suggest that targeting hepatic monoacylglycerol acyltransferase activity during early life might provide a novel strategy to improve hepatic insulin sensitivity and prevent late-onset insulin resistance and fatty liver disease.-Ramon-Krauel, M., Pentinat, T., Bloks, V. W., Cebrià, J., Ribo, S., Pérez-Wienese, R., Vilà, M., Palacios-Marin, I., Fernández-Pérez, A., Vallejo, M., Téllez, N., Rodríguez, M. À., Yanes, O., Lerin, C., Díaz, R., Plosch, T., Tietge, U. J. F., Jimenez-Chillaron, J. C. Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.
出生后过度喂养会增加日后患慢性疾病的风险，包括肥胖、胰岛素抵抗、肝脂肪变性和2型糖尿病。表观遗传机制可能是早期营养相关长期影响的基础。在这里，我们旨在探索胰岛素抵抗和肝脂肪变性早期发展所涉及的分子途径，并研究DNA甲基化和组蛋白修饰对代谢疾病长期编程的潜在贡献。我们使用了一种通过减少窝仔数来建立的、特征明确的新生小鼠过度喂养和早期肥胖模型。新生小鼠过度喂养在生命早期就导致了肝脏胰岛素抵抗，尽管食物摄入量恢复正常，但这种抵抗在成年期一直持续。单酰甘油O-酰基转移酶（Mogat）1的上调可能通过增加细胞内二酰甘油含量来介导肝脂肪变性和胰岛素抵抗。Mogat1的早期和持续失调与可能有利于Mogat1表达的组蛋白修饰组合有关。总之，出生后过度喂养会导致肝脏胰岛素敏感性极快速的紊乱，这种紊乱在成年前一直相对稳定。表观遗传机制，特别是组蛋白修饰，可能导致这种长期影响。我们的数据表明，在生命早期针对肝脏单酰甘油酰基转移酶活性可能提供一种新策略，以改善肝脏胰岛素敏感性并预防迟发性胰岛素抵抗和脂肪肝疾病。-拉蒙-克劳埃尔，M.，彭蒂纳特，T.，布洛克，V.W.，塞夫里亚，J.，里博，S.，佩雷斯-维内塞斯，R.，比利亚，M.，帕拉西奥斯-马林，I.，费尔南德斯-佩雷斯，A.，瓦列霍，M.，特列斯，N.，罗德里格斯，M.A.，亚内斯，O.，勒林，C.，迪亚斯，R.，普洛施，T.，蒂特格，U.J.F.，希门尼斯-奇拉龙，J.C. Mogat1基因座的表观遗传编程可能将新生儿营养过剩与长期肝脂肪变性和胰岛素抵抗联系起来。
