Neural Functioning of Feeding Centers in Obese Youth

描述(申请人提供)：青少年肥胖加剧了青少年2型糖尿病患病率的增加。肥胖青少年在发展为糖尿病前期/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和中枢性胰岛素抵抗的发展，从而促进肥胖及其相关代谢并发症的持久存在。卡普里奥博士的研究主要针对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从事能量代谢中央调节领域的工作。我们的目标是将这些耶鲁大学的不同研究人员聚集在一起，探索具有胰岛素抵抗和相对较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觅食行为的神经元回路的功能变化。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。假设如下：1.与年龄、性别和青春期相匹配的肥胖敏感和瘦青少年相比，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的下丘脑fMRI信号减弱。与葡萄糖相比，摄入2-果糖对下丘脑和其他与进食行为有关的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。肥胖青少年对特定食物提示的反应所涉及的大脑奖赏系统区域之间的功能连接发生了变化，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来检查特定食欲区域之间的联系，如背侧纹状体和尾状核与下丘脑之间的联系。特别是，我们将研究这些网络中的连接性是如何作为大脑燃料的函数变化的，我们将寻找具有胰岛素抵抗谱极端末端的瘦青少年和肥胖青少年对燃料的不同网络反应。了解肥胖青少年调节稳态和非稳态神经回路的中枢对常见的高美味食物(葡萄糖)的不同反应，可能会转化为在年轻人中制定更有效的体重增加和糖尿病预防计划。 与公共健康相关：关于大脑对食物摄取或对食物提示的反应，成年人知道得很多。相比之下，很少有人对青少年进行研究，以了解饥饿和饱腹感背后的神经回路。更重要的是，据我们所知，在这个青春期的关键时期，几乎还没有研究了解肥胖的存在会如何纵向影响这些神经回路。虽然下丘脑功能降低可能是肥胖的次要因素，但从长远来看，它可能会导致肥胖状态的持续和严重的胰岛素抵抗，进而可能导致糖尿病和代谢综合征的发展。使用功能磁共振成像，我们计划确定肥胖青少年，瘦素和脂联素相对较低，同时循环胰岛素水平较高，是否也可能在大脑的某些区域显示异常的神经元活动，其中一些已知是能量平衡和觅食行为的关键调节因素。

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.