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: 10359099
• 负责人: SONIA CAPRIO
• 金额: $ 69.06万
• 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/10359099
• 关键词: ADD-1 protein; Abdomen; Acetyl Coenzyme A; Acute; Adipocytes; Adipose tissue; 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; 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; Play; 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.

项目总结/摘要 该提案寻求对NICHD在过去26年中持续资助的翻译赠款的支持。改变 在青春期，与肥胖无关的脂肪分配具有胰岛素抵抗（IR）、T2 D 脂肪肝在过去的十年里，我们形成了“耶鲁大学肥胖青少年体脂模式研究”， 队列，评估了体脂分布作为葡萄糖/胰岛素代谢调节剂的作用，并描述了一种 明显的“代谢表型”，典型表现为腹部SAT的浅表层薄、VAT增加、脂肪肝 标记为IR。最近，该队列的纵向随访显示，高VAT/（VAT+SAT）表型 是年轻人脂肪肝的最佳预测指标。为了解开低效脂肪的细胞机制， 在当前周期中，我们开始与Marc Hellerstein一起使用2 H2O标记 一种测量甘油三酯、从头脂肪生成（DNL）和脂肪细胞的体内动态通量的方法 腹部和臀部SAT的周转率亮点：肥胖的青春期女孩与高增值税/（增值税+SAT） 显示：a-在腹部和臀部SAT中增加的体内脂解速率; B-更高的脂肪细胞周转; c- 脂肪分解率增加与脂肪肝密切相关。在这些发现的基础上， 建议是：解开受损的胰岛素介导的 在肥胖青少年中，两个SAT库发生脂解抑制及其与脂肪肝的联系 腹部脂肪分布不佳具体目标和假设（H）是： 目的1和H1 -确定引起体内脂解增加的潜在分子机制 高VAT/（VAT+SAT）肥胖者腹部和臀部SAT库的流量与BMI、年龄、 低增值税/（增值税+SAT）的性别匹配的肥胖青年。H1：肥胖青年WAT脂解增加 高VAT/（VAT+SAT）与胰岛素刺激的胰岛素受体激酶（IRK）降低相关 在一些实施方案中，所述蛋白质磷酸化导致ATGL、CGI-58、PLIN 1和HSL磷酸化增加。目标2 & H2 a-测试 是否增加的利率在新生儿（GNG）与过度的WAT脂解， 与BMI、年龄、性别相比，SAT对高VAT/（VAT+SAT）肥胖青年的肝脏IR有贡献 将肥胖青年与低增值税/（增值税+SAT）相匹配。H2 b-肥胖青年WAT脂解率增加 高增值税/（增值税+SAT）将与肝GNG率增加相关，这反过来又可归因于 肝乙酰辅酶A含量增加，反映为β-OHB周转率增加。目标3和H3： 确定调解脂肪肝的时间发展的机制，我们将测试假设 随着时间的推移，新生脂肪生成（DNL）的变化将与脂肪肝的变化相关， 肥胖的年轻人 state-of-the-art 总体方法：在本研究招募的瘦和肥胖青年中，我们将使用以下组合： 细胞/分子技术（G.I Shulman）、钳夹+同位素、MRI和脂质的体内测量 通量（S. Caprio & N. Santoro）和脂肪细胞周转（2 H2O标记法）（M. Hellerstein）在SAT仓库。