Impact of hypothalamic gliosis on appetite regulation and obesity risk in children

下丘脑神经胶质增生对儿童食欲调节和肥胖风险的影响

• 批准号: 10558608
• 负责人: Ellen A Schur
• 金额: $ 70.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558608
• 关键词: Adult; Age; Appetite Regulation; Area; Basic Science; Behavior assessment; Behavioral; Body Composition; Body Weight; Body mass index; Brain; Brain region; Calories; Categories; Cells; Central Nervous System; Characteristics; Child; Childhood; Cicatrix; Clinical; Conceptions; Corpus striatum structure; Cues; Data; Desire for food; Diet Habits; Diet Monitoring; Dietary Assessment; Eating; Eating Behavior; Energy Intake; Evaluation; Fatty acid glycerol esters; Food; Fostering; Functional Magnetic Resonance Imaging; Genetic; Gliosis; Health; High Fat Diet; Homeostasis; Hormonal; Hormones; Human; Hyperphagia; Hypothalamic structure; Impairment; Inflammation; Inflammatory; Insulin Resistance; Intake; Investigation; Longitudinal cohort; Longitudinal cohort study; MRI Scans; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Modeling; Neurobiology; Neuroglia; Neuronal Injury; Neurons; Nutritional; Obesity; Outcome; Overweight; Pathogenicity; Pathway interactions; Patient Self-Report; Persons; Play; Preventive; Pro-Opiomelanocortin; Process; Public Health; Regulation; Relaxation; Reporting; Research; Research Personnel; Rest; Risk Factors; Rodent; Rodent Model; Role; Satiation; Science; Signal Transduction; Site; Structure of nucleus infundibularis hypothalami; Symptoms; Techniques; Testing; Time; Tissues; Visit; Visual; Weight; Weight Gain; adult obesity; aged; behavior test; brain dysfunction; brain tissue; clinical investigation; design; diet-induced obesity; early childhood; excessive weight gain; feeding; follow-up; glial activation; human tissue; imaging detection; indexing; insight; modifiable risk; negative affect; neural; neuron loss; neuroprotection; novel strategies; obesity development; obesity in children; obesity risk; obesogenic; pharmacologic; pre-clinical; prevent; research study; response; tool

ABSTRACT Pediatric obesity is a harbinger of lifelong excess weight, suggesting that neurobiological processes beginning in childhood could ultimately raise the defended level of body adiposity. Recent findings from rodent models suggest a possible mechanism for this process: an inflammatory glial cell response—called gliosis— occurs in the arcuate nucleus, plays a pathogenic role in diet-induced obesity, and involves neuronal loss and potentially permanent glial scarring. The arcuate nucleus is located in the mediobasal hypothalamus (MBH) and is the primary hypothalamic region regulating energy homeostasis; thus, neuronal damage or tissue remodeling in this brain area could significantly impact regulation of body weight and appetite. Importantly, gliosis is detectable in brain tissue in humans by magnetic resonance imaging (MRI). Using MRI, the investigators discovered the first evidence of MBH gliosis in obese adults. The investigators' new findings show that gliosis negatively impacts brain regulation of appetite in adults and that MBH gliosis is also present in children with greater adiposity. Our overarching hypothesis is that the presence of MBH gliosis contributes to reduced satiety responsiveness and poor intake regulation in children and could also represent a risk factor for excessive weight gain. The proposed 2-site research study uses a longitudinal cohort design in 102 children aged 9–11 yr including baseline MRI and functional MRI (fMRI), in-depth eating behavior testing, and measurement of hormone profiles. Serial measurement of weight and self-reported eating habits will occur over 2 yr, with a repeated MRI at 2 yr. The study aims to: 1) test if MBH gliosis is associated with impaired intake regulation and poor weight outcomes over 2 yr in children, 2) determine if CNS appetitive processing is negatively affected when evidence of MBH gliosis is present, and 3) test for other brain regions in which gliosis is present in association with excess adiposity in children. An exploratory aim will assess changes in gliosis in children over 2 yr and their relation to changes in body weight and adiposity. In sum, basic science advances have identified hypothalamic cellular responses that facilitate weight gain during times of nutritional abundance. However, this neurobiological process is capable of forming glial scars that are detrimental to neuronal functioning. The proposed study represents the first investigation of whether gliosis within body- weight regulating areas of the hypothalamus has implications for appetite regulation and weight trajectories in children. As such, the potential insights could trigger entirely new lines of investigation at both the basic science and translational level. Clinically, findings could foster an expansion of our conception of children's eating behavior from a modifiable risk factor (i.e., indicative of poor choices) to a neurobiologically-mediated symptom requiring targeted pharmacologic, behavioral, and preventive approaches.

摘要 儿童肥胖是终身超重的先兆，这表明神经生物学过程 从儿童时期开始，可以最终提高身体肥胖的防御水平。啮齿动物的最新发现 模型提示了这一过程的可能机制：炎症性神经胶质细胞反应--称为神经胶质增生， 发生在弓状核，在饮食诱导的肥胖中起致病作用，并涉及神经元损失， 潜在的永久性神经胶质疤痕弓状核位于下丘脑内侧基底核（MBH） 并且是调节能量稳态的主要下丘脑区域;因此， 这一脑区的重塑可能会显著影响体重和食欲的调节。重要的是， 通过磁共振成像（MRI）可以检测人脑组织中的神经胶质增生。使用MRI， 研究人员发现了肥胖成人MBH神经胶质增生的第一个证据。调查人员的新发现表明， 神经胶质增生对成人食欲的大脑调节有负面影响，MBH神经胶质增生也存在于 肥胖的儿童。我们的总体假设是，MBH神经胶质增生的存在有助于 儿童的饱腹感反应降低和摄入调节不良，也可能是 体重过度增加。拟议的2个地点的研究采用纵向队列设计，在102名儿童 年龄9-11岁，包括基线MRI和功能MRI（fMRI），深入的饮食行为测试， 测量激素曲线。连续测量体重和自我报告的饮食习惯将发生 2年以上，2年时重复MRI。该研究旨在：1）测试MBH胶质增生是否与受损的 2）确定中枢神经系统食欲处理是否 当存在MBH神经胶质增生的证据时受到负面影响，以及3）测试其中存在神经胶质增生的其他脑区域 与儿童过度肥胖有关。一个探索性的目标是评估神经胶质增生的变化， 2岁以上的儿童及其与体重和肥胖变化的关系。总而言之，基础科学的进步 已经确定了下丘脑细胞的反应，促进体重增加期间的营养 丰饶。然而，这一神经生物学过程能够形成胶质瘢痕，这对神经胶质细胞损伤是有害的。 神经元功能这项拟议中的研究代表了第一次调查是否体内神经胶质增生- 下丘脑的体重调节区对食欲调节和体重轨迹有影响， 孩子因此，这些潜在的见解可能会在基本的 科学和翻译水平。临床上，研究结果可以促进我们对儿童的概念的扩展。 饮食行为与可改变的风险因素（即，指示糟糕的选择）到神经生物学介导的 症状需要有针对性的药理学，行为和预防方法。