Neural Functioning of Feeding Centers in Obese Youth

肥胖青少年喂养中心的神经功能

• 批准号: 8050152
• 负责人: SONIA CAPRIO
• 金额: $ 52.3万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050152
• 关键词: Acute; Adolescence; Adolescent; Adult; Affect; Age; American; Amygdaloid structure; Animal Model; Animals; Attenuated; Automobile Driving; Behavior; Bilateral; Biological Markers; Blood flow; Body Weight Changes; Brain; Brain region; Cerebrovascular Circulation; Child; Childhood; Clinical; Complex; Consumption; Corpus striatum structure; Coupled; Cues; Deposition; Desire for food; Development; Diabetes Mellitus; Diagnostic radiologic examination; Diet; Disease; Dopamine; Dorsal; Dyslipidemias; Eating; Energy Intake; Energy Metabolism; Epidemiology; Exhibits; Fatty acid glycerol esters; Feeding behaviors; Female Adolescents; Food; Fructose; Functional Magnetic Resonance Imaging; Functional disorder; Fusiform gyrus; Gender; Glucose; Glucose Intolerance; Goals; High Prevalence; Homeostasis; Hormones; Hunger; Hyperinsulinism; Hyperphagia; Hypothalamic structure; Inflammation; Ingestion; Insula of Reil; Insulin; Insulin Resistance; Intake; Internal Medicine; Investigation; Lead; Leptin; Link; Lipids; Longitudinal Studies; Magnetic Resonance Imaging; Malonyl Coenzyme A; Maps; Measurement; Measures; Mediating; Metabolic; Metabolic syndrome; Neurons; Neurophysiology - biologic function; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Oral; Parahippocampal Gyrus; Pediatrics; Peripheral; Phenotype; Physiological; Play; Population; Prediabetes syndrome; Prevalence; Prospective Studies; Psychiatry; Puberty; Public Health; Regulation; Relative (related person); Reporting; Research; Research Personnel; Resistance; Rest; Rewards; Risk; Risk Factors; Role; Satiation; Scientist; Secondary to; Series; Severities; Signal Transduction; Source; Staging; Subgroup; Sweetening Agents; System; Time; Translating; Ventral Striatum; Visceral; Weight Gain; Work; Youth; adenylate kinase; adiponectin; base; caudate nucleus; cohort; critical period; diabetes prevention program; endophenotype; fasting glucose; feeding; ghrelin; girls; glucose metabolism; glucose tolerance; hedonic; impaired glucose tolerance; insight; insulin secretion; insulin sensitivity; intrahepatic; male; multidisciplinary; neural circuit; neurobehavioral; obesity in children; patient oriented research; public health relevance; research study; response; reward circuitry; subcutaneous

DESCRIPTION (provided by applicant): Adolescent obesity is fueling the increase in the prevalence of T2DM in youth. Obese adolescents on their path to developing prediabetes/T2DM present with severe peripheral insulin resistance, marked hyperinsulinemia and relatively low leptin levels. These abnormal adiposity related signals may not only favor the development of peripheral but also central insulin resistance, thereby promoting the perpetuation of obesity and its associated metabolic complications. Dr. Caprio's research is mainly in peripheral insulin and glucose metabolism in obese adolescents. However, there are a number of basic, clinical, physicist and neurobehavioral scientists at Yale actively working in the field of Central Regulation of Energy Metabolism. Our goal is to bring together these various Yale-based investigators to explore whether obese adolescents with insulin resistance and relative low leptin levels exhibit functional alterations of the neuronal circuits involved in the regulation of energy metabolism and food seeking behaviors. We here propose a series of hypotheses-driven studies which will be performed by a multidisciplinary team of investigators from Internal Medicine, Diagnostic Radiology, Psychiatry and Pediatrics, using an integrated team approach. The hypotheses are: 1- The hypothalamic fMRI signal after the ingestion of glucose is attenuated in obese adolescents with insulin resistance, relative low levels of leptin and marked hyperinsulinemia compared to age, gender and puberty matched obese sensitive and lean adolescents. 2- Fructose consumption has differential effects when compared to glucose on the functional connections between the hypothalamus and other brain regions implicated in feeding behavior and that these differential effects are magnified in obese adolescents. 3- Functional connectivity between brain regions of the reward system implicated in the response to specific food cues are altered in the obese adolescents and this is related to hyperinsulinemia/insulin resistance. The team will use functional connectivity fMRI mapping to examine the connections between specific appetitive regions such as the dorsal striatum and caudate nucleus and the hypothalamus. In particular, we will examine how connectivity within these networks changes as a function of brain fuel, and we will look for differential network responses to the fuels between lean and obese adolescents with extreme ends of the insulin resistance spectrum. Understanding the differential response of centers regulating the homeostatic and non-homeostatic neuronal circuits to common highly palatable foods (glucose) in obese adolescents may translate into the development of more effective weight gain and diabetes prevention program in youth. PUBLIC HEALTH RELEVANCE: Much is known in adults regarding how the brain reacts to both ingestion of foods or in response to food cues. In contrast, little investigation has been done in adolescents to understand the neural circuitry underlying hunger and satiation. Even more important, virtually no studies, to our knowledge, have yet been done to understand how these neural circuits might be affected longitudinally by the presence of obesity during this critical period of adolescence. Although a reduced hypothalamic function may well be secondary to the obesity, in the long run it may contribute to the persistence of the obese state and severity of the insulin resistance which, in turn may lead to the development of diabetes and metabolic syndrome. Using fMRI we plan to determine if obese adolescents, with relative low leptin and adiponectin in conjunction with high circulating insulin levels, might also display abnormal neuronal activity in certain regions of the brain, some of which are known to be key regulators of energy homeostasis and food seeking behavior.

描述（由申请人提供）：青春期肥胖正在推动青年中T2DM患病率的增加。肥胖的青少年在发展前糖尿病前/T2DM的道路上，具有严重的外周胰岛素抵抗，明显的高胰岛素血症和相对较低的瘦素水平。这些异常的肥胖相关信号可能不仅有利于外围胰岛素抵抗的发展，还有利于中央胰岛素抵抗，从而促进肥胖症的延续及其相关的代谢并发症。 Caprio博士的研究主要是肥胖青少年的外周胰岛素和葡萄糖代谢。但是，耶鲁大学有许多基本，临床，物理学家和神经行为科学家在能量代谢中心调节领域积极工作。我们的目标是将这些基于耶鲁的各种研究人员汇集在一起​​，以探索具有胰岛素抵抗和相对低瘦素水平的肥胖青少年是否表现出参与调节能量代谢和寻求食物行为的神经元回路的功能改变。我们在这里提出了一系列以假设为导向的研究，这些研究将由内科，诊断放射学，精神病学和儿科的多学科研究人员使用综合团队方法进行。假设是：1-与年龄，性别和青春期相匹配的肥胖敏感和精益的青少年相比，在具有胰岛素抵抗，相对低水平的瘦素和明显的高胰岛素血症的肥胖青少年中摄入葡萄糖后的下丘脑FMRI信号。 2-与葡萄糖相比，果糖消耗对下丘脑和其他与喂养行为有关的大脑区域之间的功能连接的影响具有不同的影响，并且在肥胖的青少年中，这些差异效应受到了放大。 3-肥胖青少年中涉及对特定食品提示的响应的奖励系统大脑区域之间的功能连通性，这与高胰岛素/胰岛素耐药性有关。团队将使用功能连通性fMRI映射来检查特定的食用区域（例如背纹状体和尾状核）和下丘脑之间的连接。特别是，我们将研究这些网络中的连通性如何随脑燃料的函数而变化，我们将寻找对具有胰岛素抗性光谱极端的精益和肥胖青少年之间燃料的差异网络响应。了解调节肥胖青少年中常见的高度可口食品（葡萄糖）的体内平衡和非室内神经元回路的中心的差异反应可能会转化为年轻人中更有效的体重增加和预防糖尿病计划的发展。 公共卫生相关性：成年人在大脑对食物的摄入或对食物提示的反应方面有何反应。相比之下，对青少年几乎没有进行调查，以了解饥饿和满足的神经回路。据我们所知，更重要的是，几乎没有研究以了解在这个关键时期的肥胖症中如何纵向影响这些神经回路。尽管下丘脑功能的降低很可能是肥胖症的继发性，但从长远来看，它可能有助于肥胖状态的持续性和胰岛素抵抗的严重性，这反过来又可能导致糖尿病和代谢综合征的发展。使用fMRI我们计划确定肥胖的青少年，相对低的瘦素和脂联素与高循环胰岛素水平结合使用，也可能显示出某些大脑某些地区的神经元活性异常寻求食物行为。