CEACAM and Insulin Action

描述(申请人提供)：胰岛素抵抗是包括肥胖、2型糖尿病和脂肪性肝炎在内的代谢性疾病的常见因素。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，高胰岛素血症反映胰岛素反应受损，但相当多的数据支持另一种观点，即高胰岛素血症导致胰岛素抵抗。由这笔赠款支持的研究开创了调节肝脏胰岛素清除的CEACAM1依赖信号通路的生化、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的作用。利用肝脏特异失活或Ceacam1基因全局零突变的小鼠，我们发现胰岛素提取障碍会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新生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、脂质合成和炎症途径中的核心作用的初步数据，我们现在扩展我们的工作，在饮食诱导肥胖的背景下调查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动物的肥胖有关，并且是饮食诱导的小鼠肥胖的早期相关因素。因此，喂给小鼠高脂饮食会使肝脏CEACAM1水平降低50%，从而导致高胰岛素血症和胰岛素抵抗。相反，Ceacam1在肝脏中的过度表达可以保护小鼠免受胰岛素抵抗和内脏肥胖的影响。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。我们现在建议检验这一假设，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，在一个肝脏Ceacam1功能增强的模型中，研究预防高胰岛素血症是否抑制饮食诱导的胰岛素抵抗，并系统地剖析CEACAM1的持续表达可以预防代谢综合征的哪个方面(胰岛素抵抗、血脂异常、肝骨病和炎症)。在目标2中，我们将研究自由脂肪酸通过PPARa作用于Ceacam1转录抑制的机制。在目标3中，我们将研究PPARa取消对Ceacam1的调控是否保留了CEACAM1的表达，并对饮食诱导的胰岛素抵抗具有保护作用。我们将在Ceacam1启动子中产生PPARa反应元件发生突变的敲入小鼠，并测试这种遗传操作是否对高脂饮食诱导的胰岛素抵抗提供保护。这应该为高胰岛素血症对胰岛素抵抗的致病作用提供一个关键的测试，并确定CEACAM1是一种易于处理的药物靶点，用于开发对抗代谢条件改变的药物。 公共卫生相关性：代谢性疾病，包括2型糖尿病、脂肪性肝炎和肥胖症，在美国和世界范围内是一个日益严重的公共卫生问题。胰岛素抵抗是这些疾病病因中的一个关键因素，通常以血浆胰岛素水平上升或高胰岛素血症为先兆。这项建议旨在确定胰岛素抵抗和高胰岛素血症之间的因果关系。在目前的资助期间，我们率先将CEACAM1作为肝脏胰岛素清除和血浆胰岛素水平的关键调节因子进行了生化、生理和遗传鉴定。我们已经证明，这一途径的紊乱会导致高胰岛素血症和胰岛素抵抗。我们现在的目标是验证这一假设，即肝脏CEACAM1的减少构成了饮食诱导的胰岛素抵抗的早期和完全可预防的机制。为此，我们将使用细胞和转基因动物研究。这些实验的综合结果应该为高胰岛素血症可能是胰岛素抵抗的原因而不是其早期后果这一想法提供一个关键测试，并将CEACAM1确定为开发对抗这种代谢状况的药物的易处理药物靶点。

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. PUBLIC HEALTH RELEVANCE: Metabolic diseases, including type 2 diabetes, steatohepatitis, and obesity are a growing public health concern in the US and worldwide. Insulin resistance is a key factor in the etiology of these diseases, and it is commonly heralded by a rise in plasma insulin levels, or hyperinsulinemia. This proposal seeks to determine the cause- effect relationship between insulin resistance and hyperinsulinemia. In the current funding period, we have pioneered the biochemical, physiological, and genetic identification of CEACAM1 as a key regulator of hepatic insulin clearance and plasma insulin levels. We have shown that disturbance of this pathway causes hyperinsulinemia and insulin resistance. We now aim to test the hypothesis that reduction in hepatic CEACAM1 constitutes an early, and fully preventable mechanism of diet-induced insulin resistance. To this end, we will use cellular and transgenic animal studies. The combined results of these experiments should provide a critical test of the idea that hyperinsulinemia can be a cause of insulin resistance, as opposed to an early consequence thereof, and identify CEACAM1 as a tractable drug target for the development of medications to combat this metabolic condition.