Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom; Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
PLoS One. 2014 Mar 21;9(3):e89505. doi: 10.1371/journal.pone.0089505. eCollection 2014.
Emerging evidence suggests that maternal obesity (MO) predisposes offspring to obesity and the recently described non-alcoholic fatty pancreas disease (NAFPD) but involved mechanisms remain unclear. Using a pathophysiologically relevant murine model, we here investigated a role for the biological clock--molecular core circadian genes (CCG) in the generation of NAFPD.
Female C57BL6 mice were fed an obesogenic diet (OD) or standard chow (SC) for 6 weeks, prior to pregnancy and throughout gestation and lactation: resulting offspring were subsequently weaned onto either OD (Ob_Ob and Con_Ob) or standard chow (Ob_Con and Con_Con) for 6 months. Biochemical, pro-inflammatory and pro-fibrogenic markers associated with NAFPD were then evaluated and CCG mRNA expression in the pancreas determined.
Offspring of obese dams weaned on to OD (Ob_Ob) had significantly increased (p≤0.05): bodyweight, pancreatic triglycerides, macrovesicular pancreatic fatty-infiltration, and pancreatic mRNA expression of TNF-α, IL-6, α-SMA, TGF-β and increased collagen compared to offspring of control dams weaned on to control chow (Con_Con). Analyses of CCG expression demonstrated a phase shift in CLOCK (-4.818, p<0.01), REV-ERB-α (-1.4,p<0.05) and Per2 (3.27,p<0.05) in association with decreased amplitude in BMAL-1 (-0.914,p<0.05) and PER2 (1.18,p<0.005) in Ob_Ob compared to Con_Con. 2-way ANOVA revealed significant interaction between MO and post-weaning OD in expression of CLOCK (p<0.005), PER1 (p<0.005) and PER2 (p<0.05) whilst MO alone influenced the observed rhythmic variance in expression of all 5 measured CCG.
Fetal and neonatal exposure to a maternal obesogenic environment interacts with a post-natal hyper-calorific environment to induce offspring NAFPD through mechanisms involving perturbations in CCG expression.
新出现的证据表明，母体肥胖（MO）使后代易患肥胖症和最近描述的非酒精性脂肪胰腺疾病（NAFPD），但涉及的机制尚不清楚。本研究使用与病理生理学相关的鼠模型，研究生物钟——分子核心节律基因（CCG）在 NAFPD 发生中的作用。
雌性 C57BL6 小鼠在怀孕前和整个孕期及哺乳期给予肥胖症饮食（OD）或标准饮食（SC），随后在断奶后继续给予 OD（Ob_Ob 和 Con_Ob）或标准饮食（Ob_Con 和 Con_Con）6 个月。然后评估与 NAFPD 相关的生化、促炎和促纤维化标志物，并确定胰腺中的 CCG mRNA 表达。
肥胖母鼠所产的后代在断奶后给予 OD（Ob_Ob）时，体重、胰腺甘油三酯、胰腺大泡脂肪浸润以及胰腺 TNF-α、IL-6、α-SMA、TGF-β 和胶原 mRNA 表达均显著增加（p≤0.05），与对照组所产的后代（Con_Con）相比。CCG 表达分析表明，CLOCK（-4.818，p<0.01）、REV-ERB-α（-1.4，p<0.05）和 Per2（3.27，p<0.05）的相位发生变化，而 BMAL-1（-0.914，p<0.05）和 PER2（1.18，p<0.005）的振幅降低。2 因素方差分析显示，MO 和断奶后 OD 之间的相互作用显著影响 CLOCK（p<0.005）、PER1（p<0.005）和 PER2（p<0.05）的表达，而 MO 本身则影响 5 种测量 CCG 的表达节律变异。
胎儿和新生儿暴露于母体肥胖环境中，并与产后高热量环境相互作用，通过 CCG 表达紊乱的机制，导致后代发生 NAFPD。
