Elucidating adiposity in a mouse model of prenatal undernutrition

阐明产前营养不良小鼠模型中的肥胖

• 批准号: 7872659
• 负责人: Elvira Marie Isganaitis
• 金额: $ 11.49万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872659
• 关键词: Accounting; Address; Adipocytes; Adipose tissue; Adult; Biological Markers; Body Composition; Cardiovascular Diseases; Cell Size; Central obesity; Child; Chronic Disease; Data; Development; Diabetes Mellitus; Disease; Dose; Embryo; Embryo Transfer; Employee Strikes; Environment; Epigenetic Process; Face; Fathers; Fatty acid glycerol esters; Female; Gene Expression; Generations; Genes; Genetic; Germ Cells; Glucose Intolerance; Goals; Growth; Hormones; Human; Individual; Insulin Resistance; Knockout Mice; Low Birth Weight Infant; Malnutrition; Measurement; Mentors; Metabolic; Metabolic Diseases; Modeling; Modification; Mothers; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Parents; Phenotype; Physiological; Pregnancy; Prevention strategy; Protocols documentation; Regulation; Relative (related person); Risk; Somatotropin; Somatotropin-Releasing Hormone; Techniques; Testing; Transgenic Mice; Visceral; Weight Gain; adipokines; analog; diabetes risk; disorder risk; food restriction; hormone analog; imprint; improved; in vivo; intergenerational; lipid biosynthesis; metabolomics; mouse model; novel; novel therapeutics; nutrition; obesity risk; offspring; overexpression; postnatal; prenatal; prevent; public health relevance; research study; transmission process

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.

描述（由申请人提供）：人们越来越认识到产前和产后早期环境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的风险增加有关。身体成分的改变和脂肪量的增加是造成这些风险的一个关键因素，但产前营养不良导致的产后脂肪组织生长加速尚不清楚。导师开发了一种产前营养不良的小鼠模型。 F0 雌性怀孕期间的食物限制会导致 F1 后代的低体重、脂肪量增加和糖尿病。产前营养不良的 F1 小鼠脂肪组织中 Pref1 的表达显着降低，Pref1 是一种印记基因，是脂肪生成的关键负调节因子。此外，尽管 F2 代没有进行营养干预，但 Pref1 和肥胖风险的降低会代际传递，这增加了表观遗传调控的可能性。该提案的总体目标是研究 Pref1 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 Pref1 表达是否可以调节这种风险。在目标 1 中，我们将使用胚胎移植技术剖析 F1 生殖细胞内变化与 F1 宫内环境影响在肥胖和 Pref1 表达代际传播中的相对贡献。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。在目标 2 中，我们将通过对 Pref1 过度表达的转基因小鼠实施我们的 F0 产前食物限制方案来测试 Pref1 表达是否直接导致产前营养不良后的肥胖风险。我们假设 Pref1 过度表达将阻止产前营养不良的 F1 后代发生肥胖和糖尿病。最后，在目标 3 中，我们将测试生长激素释放类似物的治疗是否可以 (a) 调节体内 Pref1 表达和 (b) 改善产前营养不良的 F1 小鼠的身体成分。这些实验的新颖之处在于，它们结合了遗传和生理学方法来检查低出生体重后脂肪组织过度生长的调节。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。 公共卫生相关性：产前营养不足会增加患糖尿病和腹部肥胖的风险。这些研究将探讨我们的产前营养不良小鼠模型中肥胖的原因。我们将确定特定基因 Pref1 是如何改变的，并测试通过基因或药理学增加 Pref1 表达是否可以预防肥胖。