Metabolic Markers and Predictors of Childhood Obesity

描述（由申请人提供）：儿童肥胖及其相关的代谢并发症正在迅速成为21世纪最大的全球挑战之一。该应用程序建立在研究人员之间跨学科合作的长期记录之上，使用最先进的胰岛素钳夹、MRS/MRI和稳定同位素方法非侵入性评估儿童肌肉葡萄糖代谢。第一轮资助始于1991年，研究胰岛素抵抗的相关性，胰岛素抵抗是儿童肥胖症最常见的代谢并发症。通过流行病学和生理学方法，我们发现肥胖儿童和青少年的胰岛素抵抗是心脏代谢危险因素和葡萄糖耐受不良的最佳预测因子，并与炎症生物标志物相关。这些研究揭示了肥胖青少年胰岛素抵抗和组织脂质分配改变之间的关键联系。在这项竞争性更新资助中提出的研究的总体和持续目标是阐明肥胖青少年胰岛素抵抗的假定机制，并解决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设。具体目标是：1）使用31 P磁共振波谱（MRS）评估线粒体功能降低是否可能导致肥胖青少年肌细胞内（IMCL）脂质含量增加;（二）为了确定以内脏脂肪比例高和腹部浅层较低为特征的肥胖表型是否与小脂肪细胞比例增加和调节脂肪细胞的基因表达减少相关，增殖和; 3）前瞻性地确定具有高比例的内脏和低皮下脂肪库的肥胖青少年是否会发展为葡萄糖耐量恶化。这些假设驱动的以患者为导向的研究将由来自多个部门的多学科研究者团队进行：内科：（Gerald Shulman博士），诊断放射学（Drs Constable和Rothman），NIDDK（Sam Cushman博士），使用综合团队方法。 公共卫生相关性：儿童肥胖症正在成为全球最常见的营养失调症。全世界约有1.1亿儿童被归类为超重或肥胖，特别是非洲裔美国人和西班牙裔青年。胰岛素抵抗，即外周组织（如肌肉，肝脏和脂肪组织）对胰岛素作用的不敏感性，是肥胖儿童是否会发展为2型糖尿病的最佳预测因素。我们以前的研究使用磁共振波谱（MRS）和成像（MRI）已经清楚地建立了肥胖青少年肌肉中的脂肪含量和胰岛素抵抗之间的联系。目前的研究将集中在确定什么可能导致脂肪在肌肉和腹腔深处积聚。

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.