Metabolic Markers and Predictors of Childhood Obesity

儿童肥胖的代谢标志物和预测因子

• 批准号: 9916292
• 负责人: SONIA CAPRIO
• 金额: $ 72.18万
• 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/9916292
• 关键词: ADD-1 protein; Abdomen; Acetyl Coenzyme A; Acute; Adipocytes; Adipose tissue; Adolescent Development; Adolescent obesity; Age; Basic Science; Body fat; 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.

项目概要/摘要 该提案寻求 NICHD 在过去 26 年来持续资助的转化赠款的支持。 青春期期间的脂肪分配（与肥胖无关）会带来胰岛素抵抗 (IR)、T2D 的高风险 在过去的十年中，我们开展了“耶鲁大学肥胖青少年体脂肪模式研究”。 队列，评估了身体脂肪分布作为葡萄糖/胰岛素代谢调节剂的作用，并描述了 明显的“代谢表型”，以腹部 SAT 浅层薄层、VAT 增加、脂肪肝为代表 最近，对该队列的纵向随访显示，高增值税/（增值税+SAT）表型 是青少年脂肪肝的最佳预测指标，旨在揭示低效脂肪背后的细胞机制。 在本周期中，我们开始与 Marc Hellerstein 一起使用 2H2O 标记来存储腹部 SAT 测量体内甘油三酯、从头脂肪生成 (DNL) 和脂肪细胞动态通量的方法 腹部和臀肌 SAT 的营业额 亮点：具有高 VAT/(VAT+SAT) 的肥胖青春期女孩。 显示：a- 腹部和臀肌 SAT 体内脂肪分解率增加；b- 脂肪细胞更新率更高； 基于这些发现，脂肪分解率的增加与脂肪肝密切相关。 提案是：揭示胰岛素介导受损的潜在分子机制 肥胖青少年中两个 SAT 储存库的脂肪分解受到抑制及其与脂肪肝的联系 腹部脂肪分布的不利模式具体目标和假设 (H) 是： 目标 1 和 H1 - 确定导致体内脂肪分解增加的潜在分子机制 与 BMI、年龄、高 VAT/(VAT+SAT) 肥胖者相比，腹部和臀肌 SAT 库的流量 以及性别匹配的低增值税/(VAT+SAT) 肥胖青年：肥胖青年中 WAT 脂肪分解增加。 高增值税/(VAT+SAT) 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 和 H2a- 进行测试。 糖异生 (GNG) 速率的增加是否与 WAT 脂肪分解过度有关 与 BMI、年龄、性别相比，SAT 会导致高 VAT/(VAT+SAT) 肥胖青少年的肝脏 IR 将肥胖青少年与低增值税/（增值税+SAT）相匹配-肥胖青少年的 WAT 脂肪分解率增加。 高增值税/（增值税+SAT）将与肝脏 GNG 率增加相关，这又可归因于 β-OHB 周转率增加反映了肝脏乙酰辅酶 A 含量增加。目标 3 和 H3：To。 确定介导脂肪肝时间发展的机制，我们将检验该假设 随着时间的推移，从头脂肪生成（DNL）的变化将与脂肪肝的变化相关 肥胖的青少年。 最先进的 总体方法：在本研究招募的瘦和肥胖青年中，我们将结合使用 细胞/分子技术 (G.I Shulman)、钳+同位素、MRI 和体内脂质测量 SAT 库中的通量（S. Caprio 和 N. Santoro）和脂肪细胞周转（2H2O 标记方法）（M. Hellerstein）。