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”是指一组慢性疾病，似乎聚集在某些