Maternal Obesity Programs Offspring Hypothalamic Neurogenesis and Appetite: Mechanisms and Prevention of Hyperphagia-mediated Childhood Obesity

摘要 在美国、巴西和LMICs，肥胖和代谢综合征是持续的流行病危机， 造成重大的公共卫生挑战和重大的经济负担。发展中的 宫内环境的编程效果体现在儿童和成人风险的增加上 超重/肥胖(OW/OB)母亲的子女肥胖一种母体OB的小鼠模型已经被 在美国和巴西建立，来自合作实验室的研究表明，产妇的OB 而高脂肪饮食会导致后代吞噬过度和肥胖，这与人类编程的影响相似。基于 在美国和巴西发表的和初步的研究，母体排卵“计划”后代的假定食欲 中央，弓状核(ARC)。我们认为母体OB可以诱导神经前体细胞(NPC) 线粒体功能障碍，改变推测的bHLH神经源性信号，并优先将ARC区分为 食欲增加(NPY/AgRP)神经元与厌食(POMC)神经元相比，导致吞噬功能亢进和肥胖。 我们建议剖析胎儿/新生儿营养的潜在分子和表观遗传机制。 改变下丘脑神经发生，使用补充的体内和体外研究，包括Cre- 重组小鼠，以确定预防/干预的目标。我们将启动对婴儿乳房的研究 牛奶和配方奶摄入量、母乳成分和可滴定婴儿体重增加的新预防策略 打破母子OW/OB的循环。该项目的目标是(I)结合巴西在以下方面的专业知识 具有美国鼻咽癌培养专业知识和实验策略的卵巢癌后代的功能特征， 线粒体功能与鼻咽癌立体定向移植：(Ii)剖析各候选通路在鼻咽癌立体定向移植中的作用 体内和体外的神经源性编程范式，(Iii)测试一种创新的、高度适用的干预措施 预防早年肥胖，以及(Iv)扩大巴西基础设施的科学、培训和技术能力 科学和临床研究。我们将共同利用体内和体外模型来探索这一途径 氧化应激改变下丘脑神经发生，并研究预防 程序性吞噬过多。该项目将促进当地和美国对巴西学生和调查人员的培训 在先进的大脑研究技术中，增强和优化婴儿喂养的方法，刺激 全民预防孕前和婴儿肥胖的公共卫生意识，建设高校 美国和巴西研究界之间的网络，以全面解决肥胖问题。

Abstract Throughout the US, Brazil and LMICs, obesity and metabolic syndrome are ongoing epidemic crises, presenting major public health challenges and significant economic burdens. The developmental programming effects of the in utero environment is demonstrated by the increased risk of childhood and adult obesity in offspring of overweight/obese (OW/OB) mothers. A murine model of maternal OB has been established in the US and Brazil, with studies from collaborating laboratories demonstrating that maternal OB and high fat diet results in offspring hyperphagia and obesity, similar to human programming effects. Based on published and preliminary studies in the US and Brazil, maternal OB “programs” the offspring putative appetite center, the arcuate nucleus (ARC). We propose that maternal OB induces neuroprogenitor cell (NPC) mitochondrial dysfunction, alters putative bHLH neurogenic signals and preferentially differentiates ARC to increased orexigenic (NPY/AgRP) vs anorexigenic (POMC) neurons, leading to hyperphagia and obesity. We propose to dissect the underlying molecular and epigenetic mechanisms by which fetal/neonatal nutrition alters hypothalamic neurogenesis, using complementary in vivo and in vitro studies, including Cre- recombinase mice, in order to identify targets for prevention/intervention. We will initiate studies of infant breast milk and formula intake, breast milk composition, and a novel preventative strategy of titrated infant weight gain to break the cycle of maternal-offspring OW/OB. The goals of this project are (i) combine Brazilian expertise on functional characterization of OB offspring with US expertise and experimental strategies on NPC culture, mitochondrial function and NPC stereotaxic transplantation, (ii) dissect the role of each candidate pathway in the neurogenic programming paradigm in vivo and in vitro, (iii) test an innovative, highly applicable intervention to prevent early life obesity, and (iv) expand the scientific, training and technical capabilities of Brazilian basic science and clinical research. Together, we will utilize in vivo and in vitro models to explore the pathway by which oxidative stress alters hypothalamic neurogenesis, and examine a novel strategy for prevention of programmed hyperphagia. This project will foster local and US training of Brazilian students and investigators in advanced techniques for brain studies, enhance and approaches to optimize infant feeding, stimulate nationwide public health awareness for the prevention of pre-conception and infant obesity, and build collegial networks between US and Brazil research communities to comprehensively tackle the problem of obesity.