Increased Adiposity Risk after Prenatal Alcohol Exposure

 描述（由申请人提供）：胎儿酒精谱系障碍（FASD）不再只是神经发育障碍的最大可预防原因。患有FASD的儿童有不适当的喂养行为，过度消耗热量和糖。他们在青春期肥胖的风险似乎也会增加。这种肥胖风险的长期代谢后果和潜在机制尚未充分研究和未知。之前的PAE动物模型也确定了肥胖增加，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，并且可能存在多种机制，PAE增加肥胖风险。本申请检验了脂质代谢失调导致PAE肥胖增加的假设。我会调查 本研究使用妊娠期酒精暴露的小鼠模型，研究PAE后肥胖风险增加的潜在机制。目的1a使用间接量热法来量化PAE如何影响全身能量平衡，以及动物适应其脂质和葡萄糖代谢以应对高饮食脂质和碳水化合物挑战的能力。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。总之，这些发现为未来的K奖申请奠定了基础，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疾病风险的理解，并将产生关于其机制和治疗的未来假设。由于肥胖增加了慢性疾病的风险并降低了生活质量，因此重要的是要了解和解决阻碍PAE患者过上健康生活方式的问题。

 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.