Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Clinical Sciences, Epigenetics and Diabetes Unit, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
EBioMedicine. 2019 Sep;47:341-351. doi: 10.1016/j.ebiom.2019.08.017. Epub 2019 Aug 19.
Individuals born with low birth weight (LBW) have an increased risk of metabolic diseases when exposed to diets rich in calories and fat but may respond to fasting in a metabolically preferential manner. We hypothesized that impaired foetal growth is associated with differential regulation of gene expression and epigenetics in metabolic tissues in response to fasting in young adulthood.
Genome-wide expression and DNA methylation were analysed in subcutaneous adipose tissue (SAT) and skeletal muscle from LBW and normal birth weight (NBW) men after 36 h fasting and after an isocaloric control study using microarrays.
Transcriptome analyses revealed that expression of genes involved in oxidative phosphorylation (OXPHOS) and other key metabolic pathways were lower in SAT from LBW vs NBW men after the control study, but paradoxically higher in LBW vs NBW men after 36 h fasting. Thus, fasting was associated with downregulated OXPHOS and metabolic gene sets in NBW men only. Likewise, in skeletal muscle only NBW men downregulated OXPHOS genes with fasting. Few epigenetic changes were observed in SAT and muscle between the groups.
Our results provide insights into the molecular mechanisms in muscle and adipose tissue governing a differential metabolic response in subjects with impaired foetal growth when exposed to fasting in adulthood. The results support the concept of developmental programming of metabolic diseases including type 2 diabetes. FUND: The Swedish Research Council, the Danish Council for Strategic Research, the Novo Nordisk foundation, the Swedish Foundation for Strategic Research, The European Foundation for the Study of Diabetes, The EU 6th Framework EXGENESIS grant and Rigshospitalet.
出生体重低（LBW）的个体在摄入高热量和高脂肪饮食时患代谢疾病的风险增加，但在成年后可能会以代谢优先的方式对禁食做出反应。我们假设，胎儿生长受损与代谢组织中基因表达和表观遗传的差异调节有关，这种调节是对成年后禁食的反应。
采用微阵列技术，分析了 LBW 和正常出生体重（NBW）男性在 36 小时禁食后和等热量对照研究后的皮下脂肪组织（SAT）和骨骼肌中的全基因组表达和 DNA 甲基化。
转录组分析显示，在对照研究后，LBW 男性的 SAT 中与氧化磷酸化（OXPHOS）和其他关键代谢途径相关的基因表达低于 NBW 男性，但在 36 小时禁食后，LBW 男性的基因表达却高于 NBW 男性。因此，只有 NBW 男性在禁食后才与 OXPHOS 和代谢基因下调有关。同样，只有 NBW 男性的骨骼肌中的 OXPHOS 基因在禁食后下调。在 SAT 和肌肉之间，观察到的组间表观遗传变化很少。
我们的研究结果为胎儿生长受损的个体在成年后暴露于禁食时，肌肉和脂肪组织中控制代谢反应差异的分子机制提供了新的见解。这些结果支持了包括 2 型糖尿病在内的代谢疾病发育编程的概念。
瑞典研究委员会、丹麦战略研究理事会、诺和诺德基金会、瑞典战略研究基金会、欧洲糖尿病研究基金会、欧盟第 6 框架项目 EXGENESIS 赠款和哥本哈根大学医院。
