Postnatal Actions of Maternal Obesity on Neonatal Metabolic Health

描述(由申请人提供)：母亲肥胖增加了后代肥胖的风险，有大量证据表明，在胎儿和新生儿发育期间进行编程有助于这种易感性。母乳喂养是公认的人类新生儿营养的“黄金标准”，与降低儿童肥胖风险有关。然而，来自人类和动物研究的新证据表明，母亲肥胖可能会盖过母乳喂养对新陈代谢健康和哺乳后代肥胖风险的好处。本研究旨在了解母体肥胖影响子代肥胖代谢易感性的机制。我们建立了一个小鼠模型，允许我们定义母亲肥胖对新生儿代谢健康和肥胖倾向的出生后贡献，区分母亲肥胖的特定影响和母亲食用高脂肪(HF)顺式饮食所带来的影响。我们的数据证明，肥胖母亲的牛奶选择性地改变了新生儿的新陈代谢。在最近的工作中，我们将这些变化与因抑制乙酰辅酶A羧基酶-1(ACC1)而导致的从头乳脂合成受损，以及肥胖母亲产生的低脂牛奶联系在一起。这项建议的总体目标是使用肥胖小鼠模型，结合创新的遗传操作以及定量代谢和成像方法，以：(1)确定母亲肥胖对后代肥胖易感性的影响；(2)详细说明肥胖母亲的牛奶对新生儿新陈代谢的影响；(3)确定ACC1和新生脂肪生成在促进新生儿肥胖的牛奶肥胖相关变化中的作用。对母体肥胖对新生儿代谢健康潜在影响的生理学和分子机制的详细系统研究，如本建议所概述的，为开发预防肥胖的新干预策略奠定了基础。

DESCRIPTION (provided by applicant): Maternal obesity increases the risk for offspring to become obese, and there is substantial evidence to suggest that programming during both fetal and neonatal development contributes to this predisposition. Breastfeeding, the recognized "gold standard" for human neonatal nutrition, is associated with reduced childhood obesity risk. However, emerging evidence from human and animal studies suggests that maternal obesity may override the benefits of breastfeeding on the metabolic health and obesity risk of nursing offspring. Our study is directed at understanding the mechanisms by which maternal obesity influences the metabolic predisposition of their off-spring to obesity. We established a mouse model that allows us to define postnatal contributions of maternal obesity to neonatal metabolic health and obesity predisposition, distinguishing the specific effects of maternal obesity from those imparted by maternal consumption of a high fat (HF) obesigenic diet. Our data document that milk from obese dams selectively programs obesigenic changes in neonatal metabolism. In recent work we linked these changes to impaired de novo milk lipid synthesis due to inhibition of acetyl- CoA carboxylase-1 (ACC1), and the production of lipid-poor milk by obese dams. The overall goals of this proposal are to use obese mouse models in conjunction with innovative genetic manipulation and quantitative metabolic and imaging approaches to: (1) define the effects of maternal obesity on off-spring obesity predisposition; (2) detail the effects of milk frm obese dams on neonatal metabolism; (3) define the roles ACC1 and de novo lipogenesis in the obesity-associated alterations in milk that promote neonatal obesity. The detailed systematic investigation of the physiological and molecular mechanisms underlying postnatal effects of maternal obesity on neonatal metabolic health, as outlined in this proposal, form the foundation for development of new intervention strategies to prevent obesity.