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: 10264059
• 负责人: Mina Desai
• 金额: $ 51.73万
• 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/10264059
• 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; 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; infant adiposity; 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; obesity prevention; offspring; offspring obesity; postnatal; preadolescence; pregnant; prepregnancy; prevent; preventive intervention; programs; rapid weight gain; 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.

摘要