Pathways of Mother to Child Transmission of Metabolic Risk

摘要 出生前和出生后早期的环境越来越被认为是重要的 慢性病风险的决定因素。低出生体重(LBW)与 增加患糖尿病和心血管疾病的风险。通过改变身体成分 脂肪量增加是这些风险的关键因素，但却加速了出生后脂肪的增加 产前营养不良后的组织生长还不是很清楚。这位导师已经 开发了一种产前营养不良的小鼠模型。孕期限食 在F1后代中，雌性F0会导致LBW、脂肪质量增加和糖尿病。产前 营养不良的F1小鼠脂肪组织表达显著减少 Pref1，这是一个印记基因，是脂肪形成的关键负面调节因子。 此外，Pref1和肥胖风险的降低是代际传递的， 尽管F2代没有营养调控，但增加了 表观遗传调控。该提案的首要目标是检查Pref1如何 表达有助于产前营养不良后的肥胖风险，并确定 脂肪组织Pref1表达的调控是通过遗传学还是药理学 方法调节了这种风险。在目标1中，我们将剖析 宫内F1生殖细胞变化与宫内环境的影响 胚胎移植对肥胖和Pref1基因表达的代际传递 技巧。此外，我们将寻找F0和F1妊娠之间的相似之处 通过代谢组学的方法来保护环境。在目标2中，我们将测试Pref1 基因表达通过以下途径直接导致产前营养不良后的肥胖风险 在转基因小鼠上实施我们的F0产前食物限制协议 Pref1的过度表达。我们假设Pref1的过度表达将防止 出生前营养不良的F1后代中肥胖和糖尿病的发生。最后， 在目标3中，我们将测试生长激素释放类似物治疗是否可以(A) 在体内调节Pref1的表达和(B)改善产前的身体成分 营养不良的F1小鼠。这些实验是新颖的，因为它们结合了基因和 检查脂肪组织过度生长调节的生理学方法 追随LBW。这些数据将被用于开发生物标记物 不利的产前环境和有针对性的预防策略。

Abstract 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.