Elucidating adiposity in a mouse model of prenatal undernutrition

描述（由申请人提供）：产前和产后早期环境越来越被认为是慢性病风险的重要决定因素。低出生体重（LBW）与糖尿病和心血管疾病风险增加有关。身体组成的改变和脂肪量的增加是这些风险的关键因素，然而产前营养不良导致的产后脂肪组织生长加速还不是很清楚。导师开发了一种产前营养不良的小鼠模型。F0雌性妊娠期间的食物限制会导致F1后代体重过低、脂肪量增加和糖尿病。产前营养不良的F1小鼠脂肪组织中pre1的表达显著降低，pre1是一种印记基因，是脂肪形成的关键负调控因子。此外，尽管在F2代中没有营养操纵，但Pref1和肥胖风险的降低是代际传递的，这提高了表观遗传调控的可能性。本研究的总体目标是研究pre1表达如何导致产前营养不良后的肥胖风险，并确定通过遗传或药理学方法操纵脂肪组织pre1表达是否可以调节这种风险。在Aim 1中，我们将通过胚胎移植技术分析F1生殖细胞内变化与F1宫内环境在肥胖症代际遗传和Pref1表达中的影响的相对贡献。此外，我们将通过代谢组学方法寻找F0和F1妊娠环境之间的相似性。在Aim 2中，我们将通过对pre1过表达的转基因小鼠施加F0产前食物限制方案，测试pre1表达是否直接导致产前营养不良后的肥胖风险。我们推测，在产前营养不良的F1后代中，过度表达Pref1可以预防肥胖和糖尿病的发生。最后，在Aim 3中，我们将测试使用生长激素释放类似物治疗是否可以(a)调节体内Pref1表达，(b)改善产前营养不良F1小鼠的身体成分。这些实验是新颖的，因为它们结合了遗传学和生理学的方法来研究肥胖后过度脂肪组织生长的调节。这些数据将用于开发不良产前环境的生物标志物和有针对性的预防策略。

DESCRIPTION (provided by applicant): The prenatal and early postnatal environments are increasingly recognized as important determinants of chronic disease risk. Low birth weight (LBW) is associated with increased risk of diabetes and cardiovascular disease. Altered body composition with increased fat mass is a key contributor to these risks, yet accelerated postnatal adipose tissue growth following prenatal undernutrition is not well understood. The mentor has developed a mouse model of prenatal undernutrition. Food restriction during pregnancy of F0 females causes LBW, increased fat mass, and diabetes in F1 offspring. Prenatally undernourished F1 mice have significant reductions in adipose tissue expression of Pref1, an imprinted gene that is a critical negative regulator of adipogenesis. Furthermore, reductions in Pref1 and obesity risk are transmitted intergenerationally, despite no nutritional manipulation in the F2 generation, raising the possibility of epigenetic regulation. The overarching goal of this proposal is to examine how Pref1 expression contributes to obesity risk following prenatal undernutrition, and to determine whether manipulation of adipose tissue Pref1 expression via genetic or pharmacologic approaches modulates this risk. In Aim 1, we will dissect the relative contribution of changes within F1 germ cells vs. effects of the F1 intrauterine environment in the inter- generational transmission of obesity and Pref1 expression by using embryo transfer techniques. In addition, we will look for similarities between F0 and F1 gestational environments through a metabolomic approach. In Aim 2, we will test whether Pref1 expression directly contributes to obesity risk following prenatal undernutrition by imposing our F0 prenatal food restriction protocol on transgenic mice with overexpression of Pref1. We hypothesize that Pref1 overexpression will prevent the development of obesity and diabetes in prenatally undernourished F1 offspring. Finally, in Aim 3, we will test whether treatment with a growth hormone releasing analog can (a) modulate Pref1 expression in vivo and (b) improve body composition in prenatally undernourished F1 mice. These experiments are novel in that they combine genetic and physiologic approaches to examine the regulation of excessive adipose tissue growth following LBW. These data will be used toward the development of biomarkers of adverse prenatal environments and targeted preventive strategies. PUBLIC HEALTH RELEVANCE: Prenatal under nutrition can increase risk of diabetes and abdominal obesity. These studies will examine the causes of obesity in our mouse model of prenatal undernutrition. We will determine how a specific gene, Pref1, is altered, and test whether increasing Pref1 expression genetically or pharmacologically can prevent obesity.