Quantitative Studies of Metabolic Organ Dynamics

所谓“代谢综合征”是指一组慢性疾病，似乎聚集在某些 个体这些疾病的核心似乎是胰岛素抵抗的存在。躯干 肥胖症，包括储存在腹膜内空间的脂肪可能是该综合征的主要原因。然而， 内脏肥胖、胰岛素抵抗和胰岛素抵抗之间联系的潜在机制 高胰岛素血症仍不清楚。我们将研究负责这些信号传导的器官间信号传导。 肥胖和胰岛素抵抗之间的联系。具体目标一：我们将研究长期的纵向变化 与对照、中等脂肪和高脂肪饮食（饱和和不饱和）相关。我们将研究 内脏和外周贮库中脂肪沉积以及肝脏、脂肪和外周胰岛素的变化 阻力我们将检验“溢出假说”：能量最初储存在内脏脂肪中，导致肝脏脂肪酸的产生。 阻力，随后在皮下脂肪中引起外周阻力。我们将测量 脂肪、肝脏和肌肉中关键基因的表达以及外周血中假定的器官间信号 和门静脉血，包括游离脂肪酸（FFA）和脂肪因子（IL-1、IL-6、脂联素、TNF α）。 我们将研究夜间FFA和脂肪因子的显著增加在糖尿病患者中的重要性。 代谢综合征的发展。具体目标二：我们将研究交感神经的作用 神经系统在之前的资助期间，我们确认了FFA的脉冲式释放（6个周期/小时） 并证实它们是交感神经驱动的（用β 3-3拮抗剂阻断）。 我们将检验这一假设，即FFA（和/或脂肪因子）的夜间脉冲式释放在 与网膜肥胖相关的胰岛素抵抗的发展。具体目标三：我们将调查 FFA、脂肪因子和交感神经系统在潜伏性胰腺β-细胞缺陷模型中的作用。 我们计划确定胰岛功能的相对减少是否与2型糖尿病前期的状态有关。 会加剧FFA和/或脂肪因子的作用，引起脂肪的中央储存和胰岛素抵抗。 胰岛素抵抗及其相关疾病在西方社会中造成了数不清的痛苦和死亡率。 了解肥胖和胰岛素之间关系的生理机制 抗药性可能提供一条途径，通过干预可以防止相关的发病率和死亡率。

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.