Neural Functioning of Feeding Centers in Obese Youth

描述（由申请人提供）：青少年肥胖加剧了青年T2 DM患病率的增加。肥胖青少年在发展为前驱糖尿病/T2 DM的过程中表现出严重的外周胰岛素抵抗、显著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，而且也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。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。然而，耶鲁大学有许多基础，临床，物理学家和神经行为科学家积极致力于能量代谢的中央调节领域。我们的目标是将这些耶鲁大学的研究人员聚集在一起，探讨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能量代谢和食物寻求行为调节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，将由来自内科，诊断放射学，精神病学和儿科的多学科研究团队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型和瘦型青少年相比，具有胰岛素抵抗、相对低水平的瘦素和显著高胰岛素血症的肥胖青少年摄入葡萄糖后的下丘脑fMRI信号减弱。2-与葡萄糖相比，果糖消耗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有不同的影响，这些不同的影响在肥胖青少年中被放大。3-在肥胖青少年中，涉及对特定食物线索的反应的奖励系统的脑区域之间的功能连接被改变，这与高胰岛素血症/胰岛素抵抗有关。研究小组将使用功能连接fMRI映射来检查特定食欲区域之间的连接，如背侧纹状体和尾状核和下丘脑。特别是，我们将研究这些网络内的连接如何作为大脑燃料的函数而变化，并且我们将寻找具有胰岛素抵抗谱极端末端的瘦和肥胖青少年之间对燃料的差异网络反应。了解中心调节稳态和非稳态神经元回路的差异反应，以常见的高度可口的食物（葡萄糖）在肥胖的青少年可能转化为更有效的体重增加和糖尿病预防计划在青年的发展。 公共卫生相关性：成年人的大脑对食物的摄入或对食物线索的反应是众所周知的。相比之下，很少有研究在青少年中进行，以了解饥饿和饱足的神经回路。更重要的是，据我们所知，几乎还没有研究来了解这些神经回路在青春期这个关键时期是如何受到肥胖的纵向影响的。虽然下丘脑功能降低可能是继发于肥胖，但从长远来看，它可能有助于肥胖状态的持续和胰岛素抵抗的严重性，这反过来可能导致糖尿病和代谢综合征的发展。我们计划使用功能性磁共振成像来确定肥胖青少年，相对较低的瘦素和脂联素与高循环胰岛素水平相结合，是否也可能在大脑的某些区域显示出异常的神经元活动，其中一些区域是已知的能量稳态和食物寻求行为的关键调节器。

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.