Metabolic Markers and Predictors of Childhood Obesity

描述(申请人提供)：儿童肥胖及其相关的代谢并发症，正迅速成为21世纪最大的全球挑战之一。这一应用建立在研究人员使用最先进的胰岛素钳、MRS/MRI和稳定同位素方法对儿童肌肉葡萄糖代谢进行非侵入性评估的跨学科合作的长期记录基础上。这项资助的第一个周期始于1991年，调查了胰岛素抵抗的相关性，胰岛素抵抗是儿童肥胖最常见的代谢并发症。运用流行病学和生理学方法，我们发现肥胖儿童和青少年中的胰岛素抵抗是心脏代谢危险因素和糖耐量异常的最佳预测因子，并与炎症的生物标志物相关。这些研究揭示了肥胖青少年中胰岛素抵抗和组织脂分配改变之间的关键联系。在这项竞争性更新拨款中提出的研究的总体和持续的目标是阐明肥胖青少年胰岛素抵抗的假定机制，并提出关于线粒体功能障碍和脂肪生成受损在其发病机制中的潜在作用的新假说。其具体目的是：1)利用31P磁共振波谱(31P磁共振波谱)评估线粒体功能降低是否可能导致肥胖青少年肌内脂肪含量增加；2)确定以内脏脂肪比例高、腹部浅层低为特征的肥胖表型是否与小型脂肪细胞比例增加及调控脂肪细胞增殖的基因表达减少相关；3)前瞻性确定内脏脂肪含量高、皮下脂肪含量低的肥胖青少年是否会出现糖耐量增加。这些假设驱动的以患者为导向的研究将由来自以下几个部门的多学科研究人员团队执行：内科(Gerald Shulman博士)、诊断放射学(DRS Conable和Rothman博士)、NIDDK(Sam Cushman博士)，使用综合团队方法。与公共健康相关：儿童肥胖正成为全球最常见的营养障碍。全球约有1.1亿儿童被归类为超重或肥胖，特别是非裔美国人和西班牙裔青年。胰岛素抵抗，即周围组织(如肌肉、肝脏和脂肪组织)对胰岛素的影响不敏感，是肥胖儿童是否会发展为2型糖尿病的最佳预测指标。我们之前使用磁共振波谱(MRS)和成像(MRI)的研究已经清楚地确立了肥胖青少年肌肉中的脂肪含量与胰岛素抵抗之间的联系。目前的研究将集中于确定什么可能导致脂肪在肌肉和腹膜深处积聚。

DESCRIPTION (provided by applicant): Childhood Obesity, and its associated metabolic complications, is rapidly emerging as one of the greatest global challenges of the 21st century. This application builds on a long track record of interdisciplinary collaboration among investigators using state of the art insulin clamp, MRS/MRI and stable isotope methodologies for noninvasively assessing muscle glucose metabolism in children. The first cycle of this grant started in 1991, investigating the correlates of Insulin Resistance, the most common metabolic complication of childhood obesity. Using epidemiological and physiological approaches we found that insulin resistance in obese children and adolescents is the best predictor of cardiometabolic risk factors and glucose intolerance and is associated with biomarkers of inflammation. These studies revealed a critical link between insulin resistance and altered tissue lipid partitioning in obese adolescents. The overall and continuing goal of the studies proposed in this competing renewal grant are to elucidate the putative mechanisms of insulin resistance in obese adolescents and to address a novel hypothesis regarding the potential role of Mitochondrial Dysfunction and Impaired Adipogenesis in its pathogenesis. The specific aims are: 1) to assess whether decreased mitochondrial function, using 31P Magnetic Resonance Spectroscopy (MRS), may contribute to the increased intramyocellular (IMCL) lipid content in obese adolescents; 2) to determine whether the obese phenotype characterized by high proportion of visceral fat and a low abdominal superficial layer is associated with an increased proportion of small adipose cells and reduced expression of genes regulating adipocyte proliferation and; 3) to determine prospectively whether the obese adolescents with a high proportion of visceral and low subcutaneous fat depots will develop a worsening of glucose tolerance. These hypotheses-driven patient oriented research studies will be performed by a multidisciplinary team of investigators from several departments: Internal Medicine: (Dr Gerald Shulman), Diagnostic Radiology (Drs Constable and Rothman), NIDDK (Dr Sam Cushman), using an integrated team approach. PUBLIC HEALTH RELEVANCE: Childhood Obesity is becoming the most common nutritional disorder worldwide. About 110 million children worldwide are now classified as overweight or obese, particularly African American and Hispanic Youths. Insulin Resistance, the insensitivity of peripheral tissues (e.g. muscle, liver and adipose tissue) to the effects of insulin, is the best predictor of whether the obese child will develop type 2 diabetes. Our previous studies using Magnetic Resonance Spectroscopy (MRS) and imaging (MRI) have clearly established the link between the fat content in the muscle of obese adolescents and insulin resistance. The present studies will focus on determining what might cause fat to accumulate in the muscle and deep abdominal cavity.