Maternal obesity and mammary cell mitochondrial function during lactation

描述（由申请方提供）：已知母体肥胖会干扰女性、啮齿动物和产奶动物的正常泌乳。然而，人们对这种情况发生的机制知之甚少。肥胖与几个器官中的线粒体功能障碍以及脂肪和其他组织中的炎症、代谢和发育缺陷有因果关系。最近的观察表明，脂肪组织功能的缺陷可能是由于组织灌注减少导致的缺氧。以哺乳期小鼠为模型，我们收集了几个有关乳腺上皮细胞（MEC）线粒体ATP合成活性与产奶量的观察结果。我们实验室的工作还确定了一个单基因小鼠模型的母亲肥胖和哺乳期，无活力的黄色（Avy）小鼠。由于这种动物的肥胖发生机制与人类相似，并且由于这些肥胖小鼠与瘦的同窝小鼠相比显示出有缺陷的泌乳，因此我们现在具有前所未有的能力来识别具有母体肥胖的泌乳乳腺中的肥胖依赖性发育和生化缺陷。这一建议的总体假设是，乳腺缺氧和炎症的增加，以及MEC线粒体生物发生和功能的缺陷，是肥胖介导的泌乳功能不全的根本原因。 将使用Avy小鼠检验该假设。 通过将这种简单但强大的母体肥胖遗传模型与配对喂养策略以及缺氧，线粒体功能，炎症和氧化损伤的选择标记物的测量相结合，该提案中描述的研究将为随后的RO1资助的旨在测试特定信号和基因的研究奠定基础，表达途径，这可能代表新的治疗目标，在治疗或预防肥胖介导的哺乳期妇女的泌乳不足。 公共卫生相关性：已知母体肥胖会损害实验动物以及哺乳期女性在哺乳期间的乳腺功能。这种泌乳缺陷发生的分子机制尚不清楚。本提案中描述的实验将开发一种新的小鼠模型，并测试有关母体肥胖损害哺乳机制的新假设。

DESCRIPTION (provided by applicant): Maternal obesity is known to interfere with normal lactation in women, rodents, and dairy animals. The mechanism, through which this occurs, however, is poorly understood. Obesity is causally linked with mitochondrial dysfunction in several organs as well as with inflammatory, metabolic, and developmental defects in adipose and other tissues. Recent observations suggest that defects in adipose tissue function may be due to hypoxia as a result of reduced tissue perfusion. Using the lactating mouse as a model, we have collected several observations which link mammary epithelial cell (MEC) mitochondrial ATP synthesis activity to milk production. Work in our laboratory has also identified a monogenic mouse model of maternal obesity and lactation, the agouti viable yellow (Avy) mouse. Because the mechanism of obesogenesis in this animal is similar to that in humans, and because these obese mice display defective lactogenesis in comparison to lean littermates, we now have an unprecedented ability identify obesity-dependent developmental and biochemical defects in the lactating mammary gland with maternal obesity. The overall hypothesis of this proposal is that increased mammary hypoxia and inflammation, and defective MEC mitochondrial biogenesis and function, are the underlying causes of obesity-mediated lactational insufficiency. This hypothesis will be tested using the Avy mouse. By combining this simple, but robust, genetic model of maternal obesity with a pair-feeding strategy and the measurement of select markers for hypoxia, mitochondrial function, inflammation, and oxidative damage, the studies described in this proposal will lay the groundwork for subsequent RO1-funded studies aimed at testing specific signaling and gene-expression pathways which could represent novel therapeutic targets in the treatment or prevention of obesity-mediated lactational insufficiency in breastfeeding women. PUBLIC HEALTH RELEVANCE: Maternal obesity is known to impair mammary gland function during lactation in experimental animals as well as in breastfeeding women. The molecular mechanism through which this lactation defect occurs is unknown. The experiments described in this proposal will develop a new mouse model and test novel hypotheses about the mechanisms through which maternal obesity impairs lactation.