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

摘要 在美国、巴西和中低收入国家，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沉重的经济负担。发育 子宫内环境的编程效应表现为儿童和成人的风险增加， 超重/肥胖（OW/OB）母亲的后代肥胖。已经建立了一种母体OB的小鼠模型， 在美国和巴西建立，合作实验室的研究表明， 高脂肪饮食导致后代暴食和肥胖，类似于人类编程效应。基于 在美国和巴西发表的一项初步研究中，母亲的产科医生“编程”了后代的假定食欲， 弓状核（ARC）。我们认为，母体OB诱导神经祖细胞（NPC） 线粒体功能障碍，改变推定的bHLH神经源性信号，并优先区分ARC， 增加的食欲（NPY/AgRP）相对于食欲（POMC）神经元，导致食欲亢进和肥胖。 我们建议剖析潜在的分子和表观遗传机制，胎儿/新生儿营养 改变下丘脑神经发生，使用补充体内和体外研究，包括Cre- 重组酶小鼠，以确定预防/干预的目标。我们将开始研究婴儿乳房 牛奶和配方奶摄入量、母乳成分和滴定婴儿体重增加的新预防策略 来打破母子OW/OB的循环该项目的目标是：（一）将巴西在以下方面的专门知识联合收割机 用美国的专业知识和NPC培养的实验策略对OB后代进行功能表征， 线粒体功能和NPC立体定位移植，（ii）剖析每个候选途径在 体内和体外的神经原性编程范例，（iii）测试创新的、高度适用的干预 预防生命早期肥胖，以及（四）扩大巴西基础教育的科学、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该途径， 其中氧化应激改变下丘脑神经发生，并检查一种新的策略， 程序性食欲过盛该项目将促进当地和美国对巴西学生和调查人员的培训 在大脑研究的先进技术中，加强和优化婴儿喂养的方法，刺激 在全国范围内提高预防孕前和婴儿肥胖的公共卫生意识， 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.