CEACAM and Insulin Action

描述（由申请人提供）：胰岛素抵抗是代谢性疾病的共同因素，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胰岛素反应受损，但大量数据支持高胰岛素血症导致胰岛素抵抗的另一种观点。该基金支持的研究开创了ceacam1依赖性信号通路的生化、生理学和遗传学鉴定，该信号通路调节肝脏胰岛素清除。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。研究人员利用Ceacam1肝脏特异性失活或全局零突变的小鼠，发现胰岛素提取受损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导致胰岛素抵抗。基于CEACAM1在调节胰岛素作用、脂质合成和炎症通路中的核心作用的初步数据，我们现在扩大了我们的工作，以研究饮食性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动物肥胖有关，并且是小鼠饮食诱导肥胖的早期相关因素。因此，给小鼠喂食高脂肪食物会使肝脏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在肝脏中的过表达可以保护小鼠免受胰岛素抵抗和内脏性肥胖。这表明高胰岛素血症在饮食性肥胖和胰岛素抵抗的发病机制中起着不利的作用。我们现在提出验证肝脏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假设。为此，我们将在Aim 1中研究在肝脏Ceacam1功能获得模型中，预防高胰岛素血症是否会抑制饮食诱导的胰岛素抵抗，我们将系统地分析Ceacam1的持续表达可以预防代谢综合征（胰岛素抵抗、血脂异常、肝纤维化和炎症）的哪个方面。在Aim 2中，我们将研究游离脂肪酸通过PPARa作用导致Ceacam1转录抑制的机制。在Aim 3中，我们将研究PPARa取消对Ceacam1的调控是否保留了Ceacam1的表达，并保护了饮食诱导的胰岛素抵抗。我们将产生Ceacam1启动子中PPARa反应元件发生突变的敲入小鼠，并测试这种基因操作是否能保护小鼠免受高脂肪饮食引起的胰岛素抵抗。这将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作为一个可处理的药物靶点，用于开发对抗改变代谢条件的药物。

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.