Brain systems and behaviors underlying response to obesity treatment in children

儿童肥胖治疗反应的大脑系统和行为

• 批准号: 10480767
• 负责人: Christian Ludwig Roth
• 金额: $ 66万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480767
• 关键词: 12 year old; Address; Aftercare; Agonist; Appetite Regulation; Area; Attenuated; Automobile Driving; Behavior; Behavior Therapy; Biological; Body Weight decreased; Body fat; Body mass index; Brain; Brain region; Calories; Child; Child Rearing; Childhood; Complement; Cues; Data; Defect; Desire for food; Double-Blind Method; Eating; Eating Behavior; Energy Intake; Evaluation; Exhibits; Family; Food; Functional Magnetic Resonance Imaging; GLP-I receptor; Gliosis; Gold; Grant; High Prevalence; Hormones; Hypothalamic structure; Impairment; Inflammatory; Intervention; Lead; Long-Term Effects; Magnetic Resonance Imaging; Maintenance; Measures; Metabolic syndrome; Motivation; Neurobiology; Obesity; Outcome; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Pilot Projects; Placebos; Predisposition; Process; Public Health; Relaxation; Research; Resistance; Role; Safety; Satiation; Satiety Response; Standardization; System; Testing; Therapeutic; Time; Translating; Treatment outcome; Weight; Weight maintenance regimen; Withholding Treatment; aged; barrier to care; base; behavioral pharmacology; clinically significant; follow-up; food environment; functional MRI scan; healthy weight; improved; indexing; insight; interest; neuroimaging; novel; obese person; obesity in children; obesity treatment; post intervention; prevent; primary outcome; randomized placebo-controlled clinical trial; relating to nervous system; response; secondary endpoint; standard care; success; treatment duration; treatment response

PROJECT SUMMARY Given the high prevalence of childhood obesity in the U.S. and the lack of durable weight loss with existing obesity interventions, new options that improve pediatric weight management are needed. Intensive family-based behavioral treatment (FBT) is the gold-standard intervention for children with obesity and is focused on changing food environments and parenting around children's eating. The proposed research is a renewal of the Brain Activation and Satiety In Children (BASIC) study which used functional Magnetic Resonance Imaging (fMRI) to better understand if neurobiological factors impact success in FBT. In this study, 55% of children with obesity treated with FBT showed clinically significant reductions in BMI z-score, and even after successful treatment, over two-thirds of children increased their BMI z-score 6−12 months after ending FBT. At baseline pre-FBT, children with obesity, compared to children of healthy weight, exhibited an attenuated central response to a satiating meal in which they did not reduce activation by high-calorie food cues across a set of a priori appetite-regulating brain regions. This pattern also was associated with worse FBT outcomes among obese children undergoing FBT, specifically, less reduction in BMI z-score during treatment. Further, greater BMI z-score reduction during FBT was associated with a decreased neural satiety response after treatment. These findings implicate neurobiological factors as a negative input onto children's ability to achieve and maintain clinically significant improvement in weight status via FBT. The proposed follow-up project builds upon these findings and investigates the hypothesis that adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) once weekly drug intervention to FBT will augment BMI z-score reduction, even among children who seem initially resistant to FBT, by promoting greater reductions in neural activation in response to a meal. In a double-blinded randomized placebo-controlled clinical trial among 64 children aged 10-12 years old, Specific Aim 1 will test the effect of adding GLP-1RA to FBT on change in BMI z-score over a total GLP-1RA treatment duration of 24 weeks and a subsequent 1-year observational follow-up period after treatment cessation. To provide mechanistic insight, Specific Aim 2 will test whether adding GLP-1RA intervention to FBT impacts neural activation by food cues. Finally, the proposed research will investigate the role of a cellular inflammatory process in the mediobasal hypothalamus ─called gliosis─ which might contribute to impaired hypothalamic function, attenuated satiety responsiveness, and potentially to worse weight management outcomes. Specific Aim 3 will test if hypothalamic gliosis is modified by FBT and/or FBT plus GLP-1RA in children and if reduction of gliosis is associated with better long-term outcomes. This research builds upon the team's prior findings to test a pharmacologic intervention with potential to modify neurobiological barriers to treatment success. The long-term objective is to translate these findings to improve obesity interventions and sustain better long-term results.

项目摘要 鉴于美国儿童肥胖症患病率很高，并且缺乏耐用的体重减轻 需要现有的肥胖干预措施，需要改善小儿体重管理的新选择。密集的 基于家庭的行为治疗（FBT）是肥胖儿童的金标准干预措施 专注于改变食物环境和围绕儿童饮食的育儿。拟议的研究是 使用功能磁性的儿童（基本）研究中大脑激活和饱腹感的更新 共振成像（fMRI）更好地了解神经生物学因素是否影响FBT的成功。在这项研究中， 用FBT治疗的肥胖儿童中有55％显示BMI Z分数的临床显着降低，甚至显示 成功治疗后，超过三分之二的儿童在结束后6-12个月增加了他们的BMI Z分数 fbt。在基线前FBT时，与健康体重的儿童相比，肥胖儿童暴露了 减弱对饱食餐的中心反应，在这种餐点中，他们没有通过高热量食物来减少激活 一组先验性胃口调节的大脑区域的线索。这种模式也与较差的FBT有关 接受FBT的肥胖儿童的结果，特别是在治疗过程中降低了BMI Z分数的降低。 此外，FBT期间的BMI Z得分降低与神经饱腹感反应下降有关 治疗后。这些发现暗示神经生物学因素是对儿童的能力的负输入 通过FBT实现并保持体重状况的临床显着改善。提议的后续行动 项目以这些发现为基础，并调查了添加臀部样肽-1的假设 受体激动剂（GLP-1RA）每周一次对FBT进行药物干预，将增加BMI Z分数的降低，即使 在似乎最初对FBT具有抵抗力的儿童中，通过促进神经激活的降低。 对一顿饭的回应。在一项双盲随机安慰剂对照临床试验中，有64名儿童 10-12岁的特定目标1将测试将GLP-1RA添加到FBT对BMI Z分数变化的影响 GLP-1RA的总治疗时间为24周，随后的1年观察随访期 治疗停止。为了提供机械洞察力，具体目标2将测试是否添加GLP-1RA FBT的干预会影响食物线索的神经激活。最后，拟议的研究将调查 细胞炎症过程在中质下丘脑中的作用 - 可能有助于 为了损害下丘脑功能，减弱的饱腹感反应能力，并有可能减轻体重 管理结果。特定的目标3将测试下丘脑神经胶质病是否通过FBT和/或FBT Plus修饰 儿童中的GLP-1RA和胶质病的减少与更好的长期结局有关。这项研究 基于团队的先前发现，以测试具有修改潜力的药物结肠干预措施 神经生物学障碍的治疗成功。长期目标是翻译这些发现以改进 肥胖干预措施并维持更好的长期结果。