Maternal obesity and mammary cell mitochondrial function during lactation

描述（由申请人提供）：已知母亲肥胖会干扰女性、啮齿动物和奶牛的正常泌乳。然而，人们对这种现象发生的机制却知之甚少。肥胖与一些器官的线粒体功能障碍以及脂肪和其他组织的炎症、代谢和发育缺陷有因果关系。最近的观察表明，脂肪组织功能缺陷可能是由于组织灌注减少导致的缺氧。以哺乳小鼠为模型，我们收集了一些将乳腺上皮细胞（MEC）线粒体ATP合成活性与产奶量联系起来的观察结果。我们实验室的工作还确定了一种单基因小鼠模型，即豚鼠活黄（Avy）小鼠。由于这种动物的肥胖发生机制与人类相似，并且由于这些肥胖的小鼠与瘦的同伴相比显示出缺陷的乳生成，我们现在有了前所未有的能力来识别与母鼠肥胖有关的哺乳乳腺中肥胖依赖的发育和生化缺陷。该建议的总体假设是，乳腺缺氧和炎症增加以及MEC线粒体生物发生和功能缺陷是肥胖介导的泌乳功能不全的潜在原因。这一假设将在Avy老鼠身上得到验证。通过将这个简单但强大的母亲肥胖遗传模型与配对喂养策略以及对缺氧、线粒体功能、炎症和氧化损伤的选择标记的测量相结合，本提案中描述的研究将为后续ro1资助的研究奠定基础，这些研究旨在测试特定的信号和基因表达途径，这些途径可能代表治疗或预防母乳喂养妇女肥胖介导的泌乳功能不全的新治疗靶点。

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.