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）：青少年肥胖正在加剧青少年 T2DM 患病率的增加。正在发展为糖尿病前期/T2DM 的肥胖青少年会出现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周胰岛素抵抗的发展，而且有利于中枢胰岛素抵抗的发展，从而促进肥胖及其相关代谢并发症的持续存在。卡普里奥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。然而，耶鲁大学有许多基础、临床、物理学和神经行为科学家积极致力于能量代谢的中央调节领域。我们的目标是将耶鲁大学的这些不同的研究人员聚集在一起，探讨具有胰岛素抵抗和瘦素水平相对较低的肥胖青少年是否表现出参与调节能量代谢和食物寻求行为的神经元回路的功能改变。我们在这里提出了一系列假设驱动的研究，这些研究将由来自内科、诊断放射学、精神病学和儿科的多学科研究小组采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瘦的青少年相比，具有胰岛素抵抗、瘦素水平相对较低和明显高胰岛素血症的肥胖青少年摄入葡萄糖后下丘脑功能磁共振成像信号减弱。 2- 与葡萄糖相比，果糖摄入对下丘脑和与进食行为有关的其他大脑区域之间的功能连接具有不同的影响，并且这些不同的影响在肥胖青少年中被放大。 3-肥胖青少年中与对特定食物线索的反应有关的奖励系统大脑区域之间的功能连接发生了改变，这与高胰岛素血症/胰岛素抵抗有关。该团队将使用功能连接功能磁共振成像图来检查特定食欲区域（例如背侧纹状体和尾状核）与下丘脑之间的连接。特别是，我们将研究这些网络内的连接如何随着大脑燃料的变化而变化，并且我们将寻找具有胰岛素抵抗谱极端的瘦青少年和肥胖青少年之间对燃料的差异网络反应。了解肥胖青少年中调节稳态和非稳态神经元回路的中心对常见高适口食物（葡萄糖）的差异反应可能有助于制定更有效的青少年体重增加和糖尿病预防计划。 公众健康相关性：成年人对于大脑如何对食物摄入或对食物提示做出反应已经了解很多。相比之下，很少有人对青少年进行研究来了解饥饿和饱足背后的神经回路。更重要的是，据我们所知，实际上还没有任何研究来了解这些神经回路如何在青春期的这个关键时期受到肥胖的纵向影响。尽管下丘脑功能下降很可能是肥胖的继发因素，但从长远来看，它可能会导致肥胖状态的持续存在和胰岛素抵抗的严重程度，进而可能导致糖尿病和代谢综合征的发生。我们计划使用功能磁共振成像来确定瘦素和脂联素相对较低以及循环胰岛素水平较高的肥胖青少年是否也可能在大脑的某些区域表现出异常的神经元活动，其中一些区域已知是能量稳态和食物寻求行为的关键调节器。