The mechanistic basis for improved metabolic health in females following lactation

 描述（由申请人提供）：母乳喂养不仅可以改善哺乳期幼儿的健康和发育，而且还可以为母亲的健康带来持久的益处，包括降低肥胖和II型糖尿病的发病率。断奶后，与分娩但不生育幼崽的雌性和根本不繁殖的雌性相比，哺乳的雌性显示出更少的内脏脂肪细胞、更低的空腹血糖、更高的胰岛素敏感性、更低的循环脂质。通过哺乳重置假说，有人提出哺乳在重置女性代谢疾病风险方面起着核心作用，但这种作用的机制在很大程度上尚未探索。该项目的目的是评估哺乳至断奶的雌性大鼠（PL）、生育但未哺乳的年龄匹配雌性大鼠（P）和未繁殖的年龄匹配雌性大鼠（NR）之间整个动物和细胞代谢差异的机制。大鼠将用作本研究的模型生物。在PL大鼠断奶后和3个月后再次比较所有给药组之间的全动物代谢率和肝脏、骨骼肌和白色脂肪组织的线粒体特征。将相对于配种前、妊娠后期和泌乳峰值评价这些值，以确定代谢模式是否表明泌乳期恢复至配种前值。基于它们在调节脂质氧化和线粒体生物发生中的作用，将在每组中评价过氧化物酶体增殖物激活受体和PCG转录辅激活因子的相对表达，以确定它们刺激泌乳后代谢的长期生理变化的潜力。此外，还将比较各组之间氧化损伤的变化，作为线粒体维持器官健康能力的指标。这项工作的结果将提高我们对哺乳如何改善整个动物代谢和细胞生理学的理解，并为未来的研究提供目标，评估无法长时间护理幼崽的妇女和不生育的妇女的干预措施。

 DESCRIPTION (provided by applicant): Breastfeeding not only improves the health and development of the suckling young but it also confers lasting benefits to the health of mother including reduced incidence of obesity and type II diabetes. Following weaning, females that lactate display fewer visceral adipocytes, lower fasting glucose, increased insulin sensitivity, an reduced circulating lipids relative to females that give birth but not suckle their young and females that do not reproduce at all. By the lactation reset hypothesis, it has been proposed that lactation plays a central role in resetting a female's risk of metabolic disease yet the mechanisms responsible for this effect remain largely unexplored. The goal of the proposed project is to evaluate the mechanisms responsible for differences in whole animal and cellular metabolism between female rats that that have suckled their young to weaning (PL), age-matched female rats that have given birth but not suckled their young (P), and aged-matched female rats that have not reproduced (NR). Rats will be used as our model organism for this study. Whole-animal metabolic rate and mitochondrial profiles of liver, skeletal muscle and white adipose tissue will be compared between all treatment groups after the PL rats are weaned and again 3 months later. These values will be evaluated relative to pre-breeding, late pregnancy, and peak lactation values to determine if patterns of metabolism are indicative of the re-establishment to pre-breeding values by lactation. Based on their roles in adjusting lipid oxidation and mitochondrial biogenesis, the relative expression of peroxisome proliferator- activated receptors and PCG transcriptional coactivator will be evaluated in each group for their potential to stimulate long term physiological changes in metabolism following lactation. In addition, variation in oxidative damage will also be compared between groups as indicators of mitochondrial ability to maintain organ health. The results of this work will improve our understanding of how whole animal metabolism and cellular physiology are improved by lactation and provide targets for future studies evaluating interventions for women that are unable to nurse their young for an extended period and women who don't reproduce.