Quantitative Studies of Metabolic Organ Dynamics

代谢器官动力学的定量研究

• 批准号: 8012973
• 负责人: RICHARD Nathan BERGMAN
• 金额: $ 26.24万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-28 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012973
• 关键词: Adipocytes; Adipose tissue; Animals; Blood; Calories; Canis familiaris; Cells; Chronic Disease; Conscious; Defect; Deposition; Development; Diet; Disease; Dose; Enzymes; Exhibits; Fatty acid glycerol esters; Functional disorder; Funding; Genes; Hepatic; Hour; Hyperinsulinism; Individual; Insulin; Insulin Resistance; Interleukin-1; Interleukin-6; Intervention; Limb structure; Link; Lipids; Lipolysis; Liver; Measures; Metabolic syndrome; Modeling; Morbidity - disease rate; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Omentum; Organ; Pancreas; Pathogenesis; Peripheral; Peripheral Resistance; Phosphoenolpyruvate Carboxylase; Physiological; Plasma; Plasminogen Activator Inhibitor 1; Play; Proto-Oncogene Proteins c-akt; Relative (related person); Resistance; Retroperitoneal Space; Risk; Role; SRE-1 binding protein; Signal Transduction; Signaling Molecule; Skeletal Muscle; Societies; Source; Streptozocin; Sympathetic Nervous System; Syndrome; Testing; Time; Triglycerides; Visceral; Work; adipokines; adiponectin; base; diabetic; glucose-6-phosphatase; insulin signaling; intraperitoneal; islet; mRNA Expression; man; metabolic abnormality assessment; mortality; prevent; resistin; saturated fat; subcutaneous

The so-called "metabolic syndrome" refers to a group of chronic diseases which appear to cluster in certain individuals. What appears to be central to these conditions is the existence of insulin resistance. Truncal adiposity, including fat stored in the intraperitoneal space may be a primary cause of the syndrome. Yet, the mechanism(s) underlying the linkage between visceral adiposity, insulin resistance and hyperinsulinemia remain obscure. We will examine the inter-organ signaling which is responsible for the link between obesity and insulin resistance. Specific Aim I: we will examine long-term longitudinal changes associated with control, moderate fat, and high fat diets (saturated and unsaturated). We will examine changes in fat deposition in visceral and peripheral depots and hepatic, adipose and peripheral insulin resistance. We will test the "overflow hypothesis": energy is stored initially in visceral fat resulting in hepatic resistance, and subsequently in subcutaneous fat causing peripheral resistance. We will measure expression of key genes in adipose, liver and muscle as well as putative inter-organ signals in peripheral and portal blood, including free fatty acids (FFA) and adipokines (IL-1, IL-6, adiponectin, resistin, TNFa). We will examine the importance of the markedly increased nocturnal FFA and adipokines in the development of the metabolic syndrome. Specific Aim II: We will investigate the role of the sympathetic nervous system. In the previous funding period we confirmed the pulsatile release of FFA (6 cycles/hour) from the adipose depot, and confirmed that they are sympathetically driven (blocked with a (3-3 antagonist). We will test that hypothesis that night-time pulsatile release of FFA (and/or adipokines) is critical in the development of insulin resistance associated with omental adiposity. Specific Aim III: we will investigate the role(s) of FFA, adipokines and the sympathetic nervous system in a model of latent pancreatic (3-cell defect. We plan to determine whether a relative reduction in islet function such as in the pre-Type 2 diabetic state will exacerbate the effects of FFA and/or adipokines to cause central storage of fat and insulin resistance. Insulin resistance and associated disorders causes untold suffering and mortality in westernized society. Understanding the physiological mechanisms underlying the relationship between obesity and insulin resistance may provide a path whereby intervention may prevent the associated morbidity and mortality.

所谓的“代谢综合征”是指似乎聚集在某些的一组慢性疾病 个人。对于这些条件而言，似乎是胰岛素抵抗的存在。截短 肥胖，包括存储在腹膜内空间中的脂肪可能是综合征的主要原因。然而， 内脏肥胖，胰岛素抵抗和 高胰岛素血症仍然晦涩。我们将检查负责 肥胖与胰岛素抵抗之间的联系。特定目的I：我们将检查长期纵向变化 与对照，中等脂肪和高脂肪饮食有关（饱和和不饱和）。我们将检查 内脏和外围库以及肝，脂肪和周围胰岛素的脂肪沉积变化 反抗。我们将测试“溢出假设”：能量最初存储在内脏脂肪中，导致肝 耐药性，随后在皮下脂肪中导致外周抗性。我们将衡量 脂肪，肝脏和肌肉中关键基因的表达以及外周中推定的器官间信号 和门户血液，包括游离脂肪酸（FFA）和脂肪因子（IL-1，IL-6，脂联素，抵抗素，TNFA）。 我们将研究明显增加的夜间FFA和脂肪因子的重要性 代谢综合征的发展。特定目标II：我们将调查同情的作用 神经系统。在上一个资金期间，我们确认了FFA的脉动释放（6个周期/小时） 从脂肪仓库中，并确认它们是同情驱动的（用（3-3个拮抗剂）阻止。 我们将测试假设FFA（和/或脂肪因子）的夜间脉动释放在 与肥胖性相关的胰岛素抵抗的发展。特定目标III：我们将调查 FFA，脂肪因子和交感神经系统的作用在潜在胰腺模型（3细胞缺陷）模型中。 我们计划确定胰岛功能的相对降低是否在类型2糖尿病状态下 将加剧FFA和/或脂肪因子的影响，导致脂肪和胰岛素抵抗的中心储存。 胰岛素抵抗和相关疾病会导致西方社会中的苦难和死亡率。 了解肥胖与胰岛素之间关系的生理机制 阻力可能提供一条路径，干预可以防止相关的发病率和死亡率。