Increased Adiposity Risk after Prenatal Alcohol Exposure

 描述(由申请人提供)：胎儿酒精谱系障碍(FASD)不再是神经发育障碍的最大可预防原因。患有FASD的儿童有不适当的进食行为，并过度摄入卡路里和糖。他们在青春期肥胖的风险似乎也增加了。这种肥胖风险的长期代谢后果和潜在机制尚未得到充分研究和了解。以前的PAE动物模型也发现肥胖增加，并关注葡萄糖代谢的失调，但酒精影响许多途径和器官系统，PAE增加肥胖风险的机制可能有多种。这一应用验证了脂代谢失调导致PAE肥胖症增加的假设。我会调查的 这一假设使用了孕期酗酒暴露的小鼠模型，并研究了PAE后肥胖风险增加的机制。目的1a使用间接量热法来量化PAE如何影响全身能量平衡，以及动物对高脂肪和碳水化合物挑战的适应其脂肪和葡萄糖代谢的能力。目的1b研究PAE如何改变调节脂质代谢和命运的关键蛋白质和信号的作用。综上所述，这些发现构成了未来K奖申请的基础，该申请将在细胞和分子水平上详细说明这些机制。这项工作将大大扩展我们对PAE如何增加肥胖和晚年代谢性疾病风险的理解，并将产生关于其机制和治疗的未来假说。由于肥胖增加会增加慢性病风险并降低生活质量，因此了解和解决阻碍PAE患者过上健康生活方式的问题非常重要。

 DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorder (FASD) is no longer just the largest preventable cause of neurodevelopmental disability. Children with FASD have inappropriate feeding behaviors and overconsume calories and sugar. They also appear to have an increased obesity risk at adolescence. The long term metabolic consequences and underlying mechanisms of this obesity risk are understudied and unknown. Previous animal models of PAE also identify increased adiposity and focus on dysregulation of glucose metabolism, but alcohol affects many pathways and organ systems and there are likely multiple mechanisms by which PAE increases obesity risk. This application tests the hypothesis that dysregulation of lipid metabolism contributes to the increased adiposity of PAE. I will investigate this hypothesis using a mouse model of gestational binge alcohol exposure and study the mechanism underlying this increased adiposity risk after PAE. Aim 1a uses indirect calorimetry to quantify how PAE affects systemic energy balance, as well as the animal's ability to adapt its lipid and glucose metabolism in response to high dietary lipid and carbohydrate challenge. Aim 1b investigates how PAE alters the action of key proteins and signals that regulate lipid metabolism and fate. Taken together, these findings form the foundation for a future K-award application that will detail these mechanisms at the cellular and molecular level. This work will substantially expand our understanding of how PAE increases risk for obesity and later life metabolic disease, and will generate future hypotheses regarding its mechanism and treatment. Because elevated adiposity increases chronic disease risk and reduces quality of life, it is important to understand and address issues that preclude individuals with PAE from living a healthy lifestyle.