CEACAM and Insulin Action

描述（由申请人提供）：胰岛素抵抗是代谢性疾病的常见因素，包括肥胖、2型糖尿病和脂肪性肝炎。高胰岛素血症是胰岛素抵抗的早期指标。虽然在许多情况下，高胰岛素血症反映了受损的胰岛素反应，但大量数据支持高胰岛素血症导致胰岛素抵抗的替代观点。这项资助支持的研究开创了调节肝脏胰岛素清除的CEACAM1依赖性信号通路的生化，生理和遗传鉴定。我们已经证明CEACAM1通过促进肝脏胰岛素清除来调节外周胰岛素作用。使用肝脏特异性失活或Ceacam1全局无效突变的小鼠，我们已经表明，胰岛素提取的损害导致慢性高胰岛素血症，并通过下调胰岛素受体和促进肝脏中的从头脂肪生成而导致胰岛素抵抗。基于强调CEACAM1在调节胰岛素作用、脂质合成和炎症的途径中的核心作用的初步数据，我们现在将我们的工作扩展到研究饮食诱导的肥胖背景下高胰岛素血症和胰岛素抵抗之间的因果关系。我们发现肝脏CEACAM1的缺失与人类和啮齿类动物的肥胖有关，并且是小鼠饮食诱导的肥胖的早期相关性。因此，给小鼠喂食高脂肪饮食会使肝脏CEACAM1水平降低> 50%，从而导致高胰岛素血症和胰岛素抵抗。相反，Ceacam 1在肝脏中的过表达保护小鼠免受胰岛素抵抗和内脏肥胖。这表明高胰岛素血症在饮食诱导的肥胖和胰岛素抵抗的发病机制中起着有害的作用。我们现在提出的假设，即肝脏CEACAM1的减少是高胰岛素血症在饮食诱导的胰岛素抵抗中的致病作用的基础。为此，我们将在目标1中，研究在肝脏Ceacam 1功能获得模型中预防高胰岛素血症是否抑制饮食诱导的胰岛素抵抗，并且我们将系统地剖析代谢综合征的哪个方面（胰岛素抵抗，血脂异常，脂肪肝和炎症）被CEACAM1的持续表达所预防。在目标2中，我们将研究通过PPARa作用的游离脂肪酸引起Ceacam 1转录抑制的机制。在目标3中，我们将研究通过PPARa取消Ceacam 1调节是否保留了CEACAM1表达，并防止饮食诱导的胰岛素抵抗。我们将产生敲入小鼠，其中Ceacam 1启动子中的PPARa反应元件已发生突变，并测试这种遗传操作是否能保护小鼠免受高脂饮食诱导的胰岛素抵抗。这应该提供高胰岛素血症对胰岛素抵抗的致病作用的关键测试，并将CEACAM1确定为开发药物以对抗改变的代谢状况的易处理的药物靶点。

DESCRIPTION (provided by applicant): Insulin resistance is the common factor among metabolic diseases that include obesity, type 2 diabetes and steatohepatitis. Hyperinsulinemia is an early indicator of insulin resistance. Although in many instances hyperinsulinemia reflects impaired insulin response, considerable data support the alternative view that hyperinsulinemia causes insulin resistance. Studies supported by this grant have pioneered the biochemical, physiological, and genetic identification of a CEACAM1-dependent signaling pathway that regulates hepatic insulin clearance. We have shown that CEACAM1 regulates peripheral insulin action by promoting hepatic insulin clearance. Using mice with liver-specific inactivation or global null mutation of Ceacam1, we have shown that impairment of insulin extraction causes chronic hyperinsulinemia and leads to insulin resistance by down-regulating insulin receptors and promoting de novo lipogenesis in liver. Based on preliminary data that underscore the central role of CEACAM1 in pathways regulating insulin action, lipid synthesis, and inflammation, we now expand our work to investigate the cause-effect relationship between hyperinsulinemia and insulin resistance in the context of diet-induced obesity. We show that loss of hepatic CEACAM1 is associated with human and rodent obesity, and is an early correlate of diet-induced obesity in mice. Thus, feeding mice a high-fat diet reduces hepatic CEACAM1 levels by > 50% to cause hyperinsulinemia and insulin resistance. Conversely, Ceacam1 overexpression in liver protects mice against insulin resistance and visceral obesity. This suggests that hyperinsulinemia plays a detrimental role in the pathogenesis of diet-induced obesity and insulin resistance. We now propose to test the hypothesis that reduction in hepatic CEACAM1 underlies the causative role of hyperinsulinemia in diet-induced insulin resistance. To this end, we will in Aim 1, investigate whether preventing hyperinsulinemia curbs diet-induced insulin resistance in a model of hepatic Ceacam1 gain-of-function, and we will systematically dissect which aspect of the metabolic syndrome (insulin resistance, dyslipidemia, hepatosteatosis, and inflammation) is prevented by the sustained expression of CEACAM1. In Aim 2, we will investigate the mechanism by which free fatty acids acting through PPARa cause transcriptional repression of Ceacam1. In Aim 3, we will investigate whether abolishing Ceacam1 regulation by PPARa preserves CEACAM1 expression, and protects against diet-induced insulin resistance. We will generate knock-in mice in which the PPARa response element in the Ceacam1 promoter has been mutated, and test whether this genetic manipulation confers protection against insulin resistance induced by high-fat diet. This should provide a critical test of the causative effect of hyperinsulinemia on insulin resistance, and identify CEACAM1 as a tractable drug target for the development of medications to combat altered metabolic conditions.