Metabolic Markers and Predictors of Childhood Obesity

儿童肥胖的代谢标志物和预测因素

• 批准号: 10790346
• 负责人: SONIA CAPRIO
• 金额: $ 13.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10790346
• 关键词: ADD-1 protein; Abdomen; Acetyl Coenzyme A; Acute; Adipocytes; Adipose tissue; Adolescence; Adolescent Development; Adolescent obesity; Age; Basic Science; Body fat; Body mass index; Childhood; Clinical Sciences; Closure by clamp; Complement; Coupled; Development; Endocrinology; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Female Adolescents; Funding; Gender; Gluconeogenesis; Glucose; Glucose Clamp; Goals; Grant; Hepatic; Hyperinsulinism; Impairment; Insulin; Insulin Receptor; Insulin Resistance; Isotopes; Label; Link; Lipase; Lipids; Lipolysis; Liver; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Metabolic; Metabolic Marker; Metabolism; Methodology; Methods; Molecular; National Institute of Child Health and Human Development; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Nutritional Science; OGTT; Obesity; PDE 3B; Pathogenesis; Pathway interactions; Pattern; Peripheral; Phenotype; Phosphorylation; Phosphotransferases; Plasma; Proliferating; Pyruvate Carboxylase; Research; Rodent; Role; Scientist; Techniques; Testing; Thinness; Time; Triglycerides; Youth; abdominal fat; cohort; follow-up; hepatic gluconeogenesis; high risk; in vivo; lipid biosynthesis; liver development; metabolic phenotype; obesity in children; perilipin; recruit; sex; stable isotope; sterol esterase; subcutaneous

PROJECT SUMMARY/ABSTRACT This proposal seeks support for a translational grant funded continuously by NICHD for the past 26 years. Altered partitioning of fat, independent of obesity, during adolescence carries a high risk for insulin resistance (IR), T2D and Fatty Liver. Over the last decade, we formed “The Yale Study of Body Fat Patterning in Obese Adolescents” cohort, assessed the role of body fat distribution as a modifier of glucose/insulin metabolism and described a distinct “metabolic phenotype” typified by a thin superficial layer of abdominal SAT, increased VAT, fatty liver and marked IR . Recently, longitudinal follow-up of this cohort revealed that the High VAT/(VAT+SAT) phenotype is the best predictor of fatty liver in youth. To unravel the cellular mechanisms underlying the inefficient fat storage in abdominal SAT we began, in the current cycle, with Marc Hellerstein to employ the 2H2O labeling method to measure in vivo the dynamic fluxes of triglycerides, De Novo Lipogenesis (DNL) and adipocyte turnover in the abdominal and gluteal SAT . Highlights: Obese adolescent girls with High VAT/(VAT+SAT) display: a- Increased in vivo rates of lipolysis in abdominal and gluteal SAT; b- higher adipocyte turnover; c- the increased lipolytic rates related strongly to Fatty Liver. Building on these findings, the overarching goal of this proposal is: To unravel the underlying molecular mechanisms by which impaired insulin-mediated suppression of lipolysis from two SAT depots occurs and its link with Fatty Liver, in obese adolescents with the unfavorable pattern of abdominal fat distribution. The Specific Aims & Hypotheses (H) are: Aim 1 & H1 - To determine the underlying molecular mechanisms causing the increased in vivo lipolysis flux in the abdominal and gluteal SAT depots of obese with High VAT/(VAT+SAT) compared to BMI, age, and gender matched obese youths with Low VAT/(VAT+SAT). H1: Increased WAT lipolysis in obese youth with High VAT/(VAT+SAT) will be associated with decreased insulin-stimulated insulin receptor kinase (IRK) phosphorylation leading to increased ATGL, CGI-58, PLIN1 and HSL phosphorylation. Aim 2 & H2a- To test whether increased rates in gluconeogenesis (GNG) associated with the excessive WAT lipolysis in the SAT contribute to hepatic IR in obese youths with High VAT/(VAT+SAT) compared to BMI, age, sex matched obese youths with the Low VAT/(VAT+SAT). H2b- Increased rates of WAT lipolysis in obese youth with High VAT/(VAT+SAT) will correlate with increased rates of hepatic GNG, which in turn can be attributed to increased hepatic acetyl-CoA content as reflected by increased rates of β-OHB turnover. Aim 3 & H3: To determine the mechanisms mediating the temporal development of fatty liver we will test the hypothesis that changes in De Novo lipogenesis (DNL) over time will be associated with changes in fatty liver in obese youths. state-of-the–art Overall Approach: In lean and obese youth recruited for this study we will use a combination of cellular/molecular techniques (G.I Shulman), clamp+isotopes, MRI and in vivo measures of lipid fluxes (S. Caprio & N. Santoro) and adipocyte turnover (2H2O labeling method) (M. Hellerstein) in SAT depots.

项目摘要/摘要 该建议寻求支持NICHD在过去26年中连续资助的翻译赠款的支持。改变 青少年期间独立于肥胖的脂肪分配具有高胰岛素抵抗的风险（IR），T2D 和脂肪肝。在过去的十年中，我们成立了“耶鲁大学对肥胖青少年体内脂肪形成的研究” 队列评估人体脂肪分布作为葡萄糖/胰岛素代谢的修饰剂的作用，并描述了A 独特的“代谢表型”，腹部SAT的薄薄层，增值税增加，脂肪肝脏 并标记为IR。最近，该队列的纵向随访揭示了高增值税/（增值税+SAT）表型 是青年脂肪肝的最佳预测指标。阐明脂肪效率低下的细胞机制 在当前周期中，我们在腹部SAT中的存储开始，马克·海勒斯坦（Marc Hellerstein）采用了2H2O标签 在体内测量甘油三酸酯，从头脂肪生成（DNL）和脂肪细胞的动态通量的方法 腹部和臀肌的营业额。亮点：肥胖的青春期女孩（增值税+SAT） 显示：a-腹部和臀肌中脂解的体内脂解率提高； B-更高的脂肪细胞更新； c- 脂肪溶解率与脂肪肝脏密切相关。在这些发现的基础上，这是总体目标 提案是：揭示胰岛素介导的受损的基本分子机制 肥胖的青少年抑制了两个SAT沉积物的脂解及其与脂肪肝的联系 腹部脂肪分布的不利模式。具体目的和假设（H）是： AIM 1＆H1-确定导致体内脂解增加的基本分子机制 与BMI，年龄，年龄相比 性别与低增值税/（增值税+SAT）的肥胖年轻人相匹配。 H1：肥胖青年的脂肪分解增加 具有高增值税/（增值税+SAT）将与胰岛素刺激的胰岛素受体激酶（IRK）减少有关 磷酸化导致ATGL，CGI-58，PLIN1和HSL磷酸化增加。目标2＆H2A-进行测试 是否增加了与多余的WAT脂解相关的糖异生（GNG） 与BMI，年龄，性别相比 匹配低谷/（增值税+SAT）的肥胖年轻人。 H2B-肥胖青年的WAT脂解率提高 使用高增值税/（增值税+SAT）将与肝脏GNG的速率增加相关，这又可以归因于 肝乙酰辅酶A含量增加，如β-OHB周转率的增加所反映。 AIM 3＆H3： 确定介导脂肪肝临时发展的机制，我们将检验假设 随着时间的推移，从头脂肪形成（DNL）的变化将与脂肪肝的变化有关 肥胖的年轻人。 最先进的 总体方法：在这项研究中招募的精益和肥胖的青年中，我们将使用 细胞/分子技术（G.I Shulman），夹具+同位素，MRI和体内脂质测量值 Fluxes（S。Caprio＆N。Santoro）和脂肪细胞周转率（2H2O标记方法）（M. Hellerstein）在SAT沉积物中。