MATERNAL LOW PROTEIN DIET IMPRINTS LIPID METABOLISM IN THE ADULT OFFSPRING

描述(由申请人提供)：在妊娠和哺乳期(围产期)暴露于低蛋白饮食(LPD)会导致脂质平衡的改变。我们的实验室和其他研究人员已经证明，围产期LPD可以降低血浆甘油三酯水平、脂肪垫重量、全身脂肪含量，并使成年后代肝脏甘油三酯含量可靠而有力地下降。值得注意的是，这种印记的血脂特征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，表明早期的生活营养环境改变了成年后肥胖的易感性。尽管该模型具有临床意义，但围产期LPD介导的脂代谢改变的机制尚不清楚。阐明这些机制可以确定降低脂肪肝和肥胖症易感性的生化途径，并有助于设计治疗策略来缓解这些情况。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下降的机制。我们推测围产期低密度脂蛋白通过减少肝脏脂肪合成和增加肝脏脂肪利用率来降低肝脏甘油三酯含量。脂肪合成可通过以下方式减少：1.甘油三酯前体脂肪酸的合成减少；2.随后由脂肪酸合成甘油三酯的减少。脂肪的利用可以通过以下方式提高：1.增加脂肪酸氧化；2.增加肝脏分泌的富含甘油三酯的极低密度脂蛋白颗粒。我们的第一个具体目标是评估基础喂养状态下成年LPD后代的这四种机制。临床和动物研究表明，基础饲喂状态的脂肪代谢可以是正常的，尽管脂肪代谢发生了潜在的生化变化。禁食会减少脂肪的合成，并显著增加脂肪的利用率。这些对FAST代谢压力的反应的大小可以揭示和揭示脂肪代谢的潜在变化。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是否影响禁食诱导的肝脏脂肪合成和脂肪利用变化的程度。 公共卫生相关性：孕妇在孕期和哺乳期的低蛋白饮食可长期减轻后代的体重。我们最近的结果表明，体重减轻的同时，雄性后代的肝脏脂肪含量也出现了持续和强劲的下降。该提案将确定早期生命营养环境影响肝脏脂肪代谢长期变化的机制。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。

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.