权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MATERNAL LOW PROTEIN DIET IMPRINTS LIPID METABOLISM IN THE ADULT OFFSPRING

母亲的低蛋白饮食会影响成年后代的脂质代谢

基本信息

批准号：
7977411
负责人：
ANIL P D'MELLO
金额：
$ 35.56万
依托单位：
UNIVERSITY OF THE SCIENCES PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-20 至 2015-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Exposure to low protein diets (LPD) during gestation and lactation (perinatal) imprints alterations in lipid homeostasis. Our laboratory and other investigators have shown that perinatal LPD decreases plasma triglyceride levels, fat pad weights, total body lipid content and produces reliable and robust decreases in liver triglyceride content in the adult offspring. Remarkably, such an imprinted lipid profile is associated with decreased susceptibility to fatty liver and obesity. These findings support clinical data demonstrating that the early life nutritional milieu alters susceptibility to obesity during adulthood. Despite the clinically relevant implications of the model, the mechanisms underlying perinatal LPD mediated alterations in lipid metabolism are not well understood. Elucidating these mechanisms could identify biochemical pathways that decrease susceptibility to fatty liver and obesity and could help design therapeutic strategies to alleviate these conditions. The overall objective of our research is to determine the mechanisms underlying the perinatal LPD mediated decrease in liver triglyceride content. We hypothesize that perinatal LPD decreases liver triglyceride content by decreasing hepatic lipid synthesis and increasing hepatic lipid utilization. Lipid synthesis can be decreased by: 1. decrease in the synthesis of fatty acids, the precursors of triglyceride 2. decrease in the subsequent synthesis of triglyceride from fatty acids. Lipid utilization can be increased by: 1. increase in fatty acid oxidation 2. increase in secretion of triglyceride rich very low density lipoprotein particles out of the liver. Our first specific aim will evaluate each of these four mechanisms in adult LPD offspring in the basal fed state. Clinical and animal studies reveal that basal fed state lipid metabolism can be normal despite underlying biochemical alterations in lipid metabolism. Fasting decreases lipid synthesis and dramatically increases lipid utilization. The magnitude of these responses to the metabolic stress of a fast can unmask and reveal underlying alterations in lipid metabolism. Using a 24 hour fast as a diagnostic tool and the four step strategy outlined earlier, our final studies will determine if perinatal exposure to LPD affects the magnitude of fasting induced alterations in hepatic lipid synthesis and lipid utilization. PUBLIC HEALTH RELEVANCE: Maternal low protein diets during pregnancy and lactation produce long term reduction in the body weight of the offspring. Our recent results demonstrate that the reduction in body weight is accompanied by consistent and robust decreases in the liver lipid content of the male offspring. The proposal will determine the mechanisms by which the early life nutritional milieu imprints long term alterations in liver lipid metabolism. Understanding these mechanisms may help develop new therapeutic strategies for the treatment of fatty liver and obesity.

描述（由申请方提供）：妊娠期和哺乳期（围产期）暴露于低蛋白饮食（LPD）会影响脂质稳态的改变。我们的实验室和其他研究人员已经表明，围产期LPD降低血浆甘油三酯水平，脂肪垫重量，全身脂质含量，并产生可靠和强大的降低肝脏甘油三酯含量在成年后代。值得注意的是，这种印迹脂质谱与脂肪肝和肥胖症的易感性降低有关。这些发现支持了临床数据，表明早期生活的营养环境改变了成年期肥胖的易感性。尽管该模型具有临床相关意义，但围产期LPD介导的脂质代谢改变的机制尚未得到很好的理解。阐明这些机制可以确定降低脂肪肝和肥胖易感性的生化途径，并有助于设计缓解这些疾病的治疗策略。我们研究的总体目标是确定围产期LPD介导的肝脏甘油三酯含量降低的机制。我们推测围产期LPD通过减少肝脏脂质合成和增加肝脏脂质利用来降低肝脏甘油三酯含量。脂质合成可以通过以下方式减少：1.减少脂肪酸（甘油三酸酯的前体）的合成2。减少随后从脂肪酸合成甘油三酯。可以通过以下方式增加脂质利用率：1.脂肪酸氧化增加2.富含甘油三酯的极低密度脂蛋白颗粒从肝脏中分泌增加。我们的第一个具体目标是评估这四种机制中的每一种在基础喂养状态下的成年LPD后代中。临床和动物研究表明，尽管脂质代谢发生了潜在的生化改变，但基础进食状态下的脂质代谢可能是正常的。禁食减少脂质合成，并显着增加脂质利用。对禁食代谢应激的这些反应的幅度可以揭示和揭示脂质代谢的潜在变化。使用24小时禁食作为诊断工具和前面概述的四步策略，我们的最终研究将确定围产期暴露于LPD是否会影响禁食诱导的肝脏脂质合成和脂质利用改变的程度。公共卫生相关性：母亲在怀孕和哺乳期间的低蛋白饮食会导致后代体重长期下降。我们最近的研究结果表明，体重减轻伴随着雄性后代肝脏脂质含量的持续和稳健降低。该提案将确定早期生命营养环境在肝脏脂质代谢中长期改变的机制。了解这些机制可能有助于开发治疗脂肪肝和肥胖症的新治疗策略。