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

母亲肥胖影响后代下丘脑神经发生和食欲：进食过多介导的儿童肥胖的机制和预防

• 批准号: 10054141
• 负责人: Mina Desai
• 金额: $ 57.11万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054141
• 关键词: 3-Dimensional; Adolescent; Adult; Age-Months; Appetite Stimulants; Autonomic nervous system; Awareness; Basic Science; Benchmarking; Body Composition; Body Weight; Brain; Brazil; Breast Feeding; Calories; Cell Culture Techniques; Cells; Child; Child Malnutrition; Chronic; Clinical Research; Clinical Trials; Cognitive; Communities; Complement; Desire for food; Development; Developmental Biology; Disease; Distant; Eating; Economic Burden; Energy Intake; Environment; Epidemic; Epigenetic Process; Etiology; Exposure to; Feedback; Fostering; Generations; Goals; High Fat Diet; Human; Human Milk; Hyperphagia; Hypothalamic structure; Impaired cognition; In Vitro; Incidence; Infant; Infant Development; Infant formula; Infrastructure; Intake; Intervention; Knockout Mice; Knowledge; Laboratories; Laboratory Study; Learning; Life; Mediating; Metabolic syndrome; Methodology; Milk; Mitochondria; Modeling; Molecular; Monitor; Mus; Neonatal; Nerve Degeneration; Neurodevelopmental Disorder; Neurons; Neurosciences; Nutritional; Obesity; Obesity Epidemic; Overnutrition; Overweight; Oxidative Stress; Pathway interactions; Perinatal; Peripheral; Phenotype; Polyneuropathy; Prevention; Prevention strategy; Preventive Intervention; Public Health; Public Health Education; Publishing; Research; Research Infrastructure; Research Personnel; Risk; Role; Satiation; Science; Signal Transduction; Structure of nucleus infundibularis hypothalami; Students; Techniques; Testing; Training; Training and Education; Transplantation; Weight Gain; Weight maintenance regimen; adult obesity; base; clinical application; conditional knockout; early-onset obesity; feeding; fetal; in utero; in vitro Model; in vivo; increased appetite; innovation; low and middle-income countries; maternal obesity; milk intake; mitochondrial dysfunction; mouse Cre recombinase; mouse model; nerve stem cell; nervous system disorder; neurodevelopment; neurogenesis; neuromechanism; novel; novel strategies; nutrition; obese mothers; obesity in children; offspring; offspring obesity; postnatal; preadolescence; pregnant; prepregnancy; prevent; programs; relating to nervous system; webinar

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.

抽象的 在美国、巴西和中低收入国家，肥胖和代谢综合征是持续存在的流行病危机， 带来了重大的公共卫生挑战和沉重的经济负担。 子宫内环境的编程影响表现为儿童和成人风险的增加 超重/肥胖 (OW/OB) 母亲的后代肥胖 已经建立了母亲 OB 的小鼠模型。 在美国和巴西成立，合作实验室的研究表明，产妇产科 而高脂肪饮食会导致后代食欲过盛和肥胖，类似于人类的编程效应。 美国和巴西已发表的初步研究表明，产妇产科“编程”了后代的假定食欲 中心，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，改变假定的 bHLH 神经源信号并优先将 ARC 分化为 促食欲（NPY/AgRP）神经元与厌食神经元（POMC）相比增加，导致食欲亢进和肥胖。 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，利用互补的体内和体外研究，包括 Cre- 重组酶小鼠，以确定预防/干预的目标，我们将启动婴儿乳房的研究。 牛奶和配方奶的摄入量、母乳成分以及滴定婴儿体重增加的新型预防策略 打破母子 OW/OB 的循环 该项目的目标是 (i) 结合巴西的专业知识。 利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 体内和体外的神经源性编程范式，（iii）测试创新的、高度适用的干预措施 预防生命早期肥胖，以及 (iv) 扩大巴西基础设施的科学、培训和技术能力 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，并研究一种预防氧化应激的新策略 该项目将促进对巴西学生和研究人员的本地和美国培训。 大脑研究的先进技术，增强和优化婴儿喂养的方法，刺激 提高全民预防孕前和婴儿肥胖的公共卫生意识，并建立合力 美国和巴西研究界之间的网络，旨在全面解决肥胖问题。