Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice
Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice
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DOI：
10.1016/j.jhep.2009.12.042
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发表时间：
2010-06-01
影响因子：
25.7
通讯作者：
Taylor, Paul D.
中科院分区：
文献类型：
--
作者：
Oben, Jude A.;Mouralidarane, Angelina;Taylor, Paul D.
背景与目的：肥胖引起的非酒精性脂肪性肝病（NAFLD）目前是富裕国家脂肪变性至肝硬化的主要原因。全世界育龄妇女和青少年的肥胖和NAFLD发病率正在上升。我们的假设是，母亲肥胖和哺乳期将代谢障碍、肥胖和NAFLD的易感性传递给后代。方法：雌性小鼠在妊娠前、妊娠期间和哺乳期分别饲喂标准或致肥性食物。通过对瘦坝和肥坝后代的交叉培养，研究了关键发育时期。3个月时断奶，饲喂标准饲料。读数包括代谢功能障碍标志物、NAFLD的生化和组织学指标、肝纤维化的诱导和纤维化途径的激活。通过分析母乳成分，研究了代谢不良和NAFLD表型的编程机制。结果：与瘦子相比，肥胖母鼠的后代存在代谢不良、胰岛素抵抗和NAFLD表型。由肥胖母鼠喂养的瘦母鼠的后代表现出过度的代谢不良和NAFLD表型，体重增加，胰岛素、瘦素、天冬氨酸转氨酶、白细胞介素-6、肿瘤坏死因子-a、肝脏甘油三酯、脂肪变性、肝纤维化、肾去甲肾上腺素和肝脏α 1-D + β 1-肾上腺素受体水平增加，表明交感神经系统激活。与瘦坝相比，肥胖坝的母乳瘦素水平也有所提高。结论：产妇肥胖可发展为代谢障碍和NAFLD表型，其严重依赖于产后早期，并可能涉及由母乳和新生儿脂肪组织衍生的瘦素介导的下丘脑食欲核信号的改变。2010年欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: Obesity induced, non-alcoholic fatty liver disease (NAFLD), is now the major cause in affluent countries, of the spectrum of steatosis-to-cirrhosis. Obesity and NAFLD rates in reproductive age women, and adolescents, are rising worldwide. Our hypothesis was that maternal obesity and lactation transmit to the offspring a pre-disposition to dysmetabolism, obesity and NAFLD.Methods: Female mice were fed standard or obesogenic chow, before, throughout pregnancy, and during lactation. The critical developmental period was studied by cross-fostering offspring of lean and obese dams. Offspring were then weaned onto standard chow and studied at 3 months. Read-outs included markers of metabolic dysfunction, biochemical and histological indicators of NAFLD, induction of liver fibrogenesis, and activation of profibrotic pathways. Mechanisms involved in programming a dysmetabolic and NAFLD phenotype were investigated by assaying breast milk components.Results: Offspring of obese dams had a dysmetabolic, insulin resistant and NAFLD phenotype compared to offspring of lean dams. Offspring of lean dams that were suckled by obese dams showed an exaggerated dysmetabolic and NAFLD phenotype, with increased body weight, as well as increased levels of insulin, leptin, aspartate transaminase, interleukin-6, tumour necrosis factor-a, liver triglycerides, steatosis, hepatic fibrogenesis, renal norepinephrine, and liver alpha 1-D plus beta 1-adrenoceptors, indicative of sympathetic nervous system activation. Obese dams also had raised breast milk leptin levels compared to lean dams.Conclusions: Maternal obesity programs development of a dysmetabolic and NAFLD phenotype, which is critically dependent on the early postnatal period and possibly involving alteration of hypothalamic appetite nuclei signalling by maternal breast milk and neonatal adipose tissue derived, leptin. (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.