Biology of IGFs in Bone

 描述（由申请人提供）： 这个Merit项目的长期目标是重点描述机制，区分胰岛素和IGF-1在骨骼细胞中的作用。在上一个资助期间，我们确定了一个新的内分泌回路，通过该回路胰岛素刺激成骨细胞产生骨钙素，骨钙素反过来又作为一种激素增加胰腺胰岛素的产生并增强外周组织的胰岛素敏感性。其他研究将胰岛素靶向mTOR定义为将成骨细胞发育程序与燃料消耗和能量代谢整合的关键检查点。我们的研究结果，以及其他实验室的补充工作，表明成骨细胞和全球能量稳态之间的调节联系。该模型中隐含的概念是骨形成、重塑和修复是能量昂贵的过程，其需要成骨细胞调节其燃料代谢和生物能量学以在其生命周期中完成阶段特异性功能。本提案中描述的新的初步数据表明，成骨细胞氧化葡萄糖和脂肪酸的能力， 酸随它们的分化状态而变化，并由不同的发育信号控制。 因此，成骨细胞中的胰岛素受体信号传导是GLUT 4依赖性葡萄糖摄取和氧化所必需的，而Wnt/LRP 5信号传导调节脂肪酸β-氧化中关键酶的活性。在这个项目中，我们将使用新的遗传小鼠模型来确定成骨细胞的能量底物氧化和代谢对成人骨骼中的全球燃料通量的影响以及对合成代谢疗法的反应。我们将测试这一假设，即成骨细胞和骨细胞的燃料消耗显着影响全球燃料需求，这些细胞调整其生物能源计划，以满足不同的需求，在其寿命和设置中，成骨细胞的能量需求提高。在具体目标1中，我们将通过检查经工程改造为缺乏成熟成骨细胞和骨细胞中葡萄糖（己糖激酶2，Hk 2）和脂肪酸（肉毒碱棕榈酰转移酶-2，Cpt 2）代谢中的专性酶的小鼠的骨和代谢表型，确定葡萄糖和脂肪酸作为成熟小鼠骨中氧化代谢底物的相对需求。在具体目标2中，我们将确定成骨细胞燃料消耗在合成代谢活动急性发作期间的重要性。具体地，我们将确定葡萄糖（Hk 2 KO）或脂肪酸氧化（Cpt 2 KO）的急性损失对负荷诱导的骨形成和响应于抗sclerostin抗体的合成代谢方案的影响。虽然这些研究是在小鼠中进行的，但它们对人类健康的重要性得到了越来越多的证据的支持，这些证据将骨钙素水平和成骨细胞酸度的其他标志物与体重指数，脂肪量，胰岛素分泌和胰岛素抵抗联系起来。我们坚信，从我们的研究中获得的信息将提高对骨骼代谢活动如何影响全球代谢活动的理解。这些信息预计将显着提高诊断和管理和治疗和预防相关的代谢紊乱流行的老年退伍军人。

 DESCRIPTION (provided by applicant): The long-term goals of this Merit project are focused on characterizing the mechanisms, which distinguish the actions of insulin and IGF-1 in skeletal cells. During the last funding period we identified a novel endocrine loop through which insulin stimulates the production of osteocalcin by osteoblasts, which in turn, functions as a hormone to increase pancreatic insulin production and enhance insulin sensitivity in peripheral tissues. Additional studies defined the insulin targe mTOR as a key checkpoint that integrates osteoblast developmental programs with fuel consumption and energy metabolism. Our findings, together with complementary work from other labs, suggest a regulatory link between osteoblasts and global energy homeostasis. Implicit in this model is the notion that bone formation, remodeling, and repair are energy- expensive processes, which require osteoblasts to adjust their fuel metabolism and bioenergetics to accomplish stage-specific functions during their life cycle. New preliminary data described in this proposal demonstrate that the ability of osteoblasts to oxidize glucose and fatty acids varies with their differentiation status and is controlled by distinct developmental signals. Thus, insulin receptor signaling in osteoblasts is required for GLUT4 dependent glucose uptake and oxidation, whereas Wnt/LRP5 signaling regulates the activity of key enzymes in β-oxidation of fatty acids. In this project, we will use new genetic mouse models to determine the impact of energy substrate oxidation and metabolism by osteoblasts on global fuel flux in adult bone and in response to anabolic therapies. We will test the hypothesis that fuel consumption by osteoblasts and osteocytes significantly impact global fuel requirements and that these cells adjust their bioenergetic programs to meet different demands during their life span and in settings where in osteoblast energy demands are heightened. In Specific Aim 1, we will determine the relative requirement for glucose and fatty acid as substrates for oxidative metabolism in mature mouse bone by examining the bone and metabolic phenotypes of mice engineered to be deficient for obligate enzymes in glucose (hexokinase 2, Hk2) and fatty acid (carnitine palmitoyltransferase-2, Cpt2) metabolism in mature osteoblasts and osteocytes. In Specific Aim 2, we will determine the importance of osteoblast fuel consumption during acute episodes of anabolic activity. Specifically, we will determine the impact of acute loss of either glucose (Hk2 KO) or fatty acid oxidation (Cpt2 KO) on load induced bone formation and in response to an anabolic regimen of anti- sclerostin antibody. While these studies have been conducted in mice, their significance to human health is supported by an increasing body of evidence linking osteocalcin levels and other markers for osteoblast acidity with body mass index, fat mass, insulin secretion, and insulin resistance. We firmly believe that the information gained from our studies will improve understanding of how the metabolic activity of the skeleton impacts global metabolic activity. Such information is expected to significantly improve the diagnosis and management and treatment and prevention of the related metabolic disturbances prevalent in aging Veterans.