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: 10093020
• 负责人: Ellen A Schur
• 金额: $ 72.1万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093020
• 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; 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; Fibrinogen; Food; Fostering; Functional Magnetic Resonance Imaging; Genetic; Gliosis; Gold; 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; Neuraxis; Neurobiology; Neuroglia; Neuronal Injury; Neurons; Nutritional; Obesity; Outcome; Overweight; Pathogenicity; Pathway interactions; Patient Self-Report; Pharmacology; Play; Preventive; Process; Public Health; Regulation; Relaxation; Reporting; Research; Research Personnel; Rest; Risk Factors; Rodent; Rodent Model; Role; Satiation; Science; Signal Transduction; Site; Structure; Structure of nucleus infundibularis hypothalami; Sum; Symptoms; Techniques; Testing; Time; Tissues; Visit; Visual; Weight; Weight Gain; adult obesity; aged; behavior test; brain tissue; clinical investigation; design; diet-induced obesity; early childhood; excessive weight gain; feeding; follow-up; glial activation; human tissue; indexing; insight; modifiable risk; negative affect; neuron loss; novel strategies; obesity development; obesity in children; obesity risk; obesogenic; pre-clinical; prevent; relating to nervous system; 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 儿童肥胖是终生超重的先兆，这表明神经生物学过程 从童年开始，最终可能会提高身体肥胖症的防御水平。啮齿动物的最新发现 模型表明了这一过程的可能机制：一种炎性胶质细胞反应--称为胶质细胞增多症-- 发生在弓状核，在饮食诱导的肥胖中起致病作用，并涉及神经元丢失和 可能是永久性的神经胶质疤痕。弓状核位于下丘脑内侧基底核(MBH)。 是调节能量平衡的主要下丘脑区域；因此，神经元损伤或组织 大脑这一区域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)可以在人类的脑组织中检测到胶质细胞增多症。使用核磁共振技术， 研究人员在肥胖成年人中首次发现了MBH胶质细胞增多症的证据。调查人员的新发现表明 胶质细胞增多症对成人食欲的大脑调节有负面影响，而且MBH胶质细胞增多症也存在于 肥胖程度更高的儿童。我们的主要假设是MBH胶质细胞增生症的存在有助于 儿童的饱腹感降低、反应性降低和摄入量调节不良，也可能是 体重过度增加。拟议的两点研究采用纵向队列设计，对102名儿童进行研究。 9-11岁，包括基线MRI和功能MRI(FMRI)，深入的饮食行为测试，以及 荷尔蒙图谱的测量。将对体重和自我报告的饮食习惯进行连续测量 两年以上，两年后重复核磁共振检查。这项研究的目的是：1)测试MBH胶质细胞增多症是否与受损有关 摄入量调节和2岁以上儿童体重结果不佳，2)决定了中枢神经系统的食欲加工是否 当存在MBH胶质细胞增多症的证据时，会受到负面影响，以及3)对其他脑胶质细胞增多症的脑区进行测试 与儿童过度肥胖有关。一项探索性目标将评估脑胶质细胞增多症的变化 2岁以上儿童及其与体重变化和肥胖的关系。总而言之，基础科学的进步 已经确定了在营养时期促进体重增加的下丘脑细胞反应 富足。然而，这种神经生物学过程能够形成神经胶质疤痕，这对 神经功能。这项拟议的研究是关于身体内胶质细胞增多症是否- 下丘脑的体重调节区对食欲调节和体重轨迹有影响 孩子们。因此，潜在的洞察可能会在两个基本领域引发全新的调查 科学和翻译水平。在临床上，这些发现可以促进我们对儿童的概念的扩展 饮食行为从可改变的风险因素(即，表明糟糕的选择)到神经生物学调节的 症状需要有针对性的药物、行为和预防方法。