Biology of IGFs in Bone

骨中 IGF 的生物学

• 批准号: 9277191
• 负责人: Thomas L Clemens
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277191
• 关键词: Acidity; Acute; Adipose tissue; Adult; Aging; Animals; Antibodies; Area; Attention; Attenuated; Autoradiography; Award; Bioenergetics; Biological; Biology; Body mass index; Bone Development; Carnitine O-Palmitoyltransferase; Cell Respiration; Cells; Consumption; Data; Development; Diabetes prevention; Diagnosis; Endocrine; Energy Metabolism; Energy-Generating Resources; Engineering; Enzymes; Euglycemic Clamping; FRAP1 gene; Family; Fatty Acids; Fatty acid glycerol esters; Funding; GLUT4 gene; Genetic; Glucose; Goals; Growth; Health; Hexokinase 2; Homeostasis; Hormones; Human; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor I; Knock-out; Lead; Life Cycle Stages; Ligands; Link; Liver; Longevity; Mammals; Measures; Metabolic; Metabolism; Modeling; Modification; Mus; Muscle; Mutation; Nature; Obesity; Organism; Osteoblasts; Osteocalcin; Osteocytes; Osteogenesis; Oxides; PET/CT scan; Pancreas; Pathway interactions; Peripheral; Physiological Processes; Physiology; Prevention; Process; Production; Receptor Signaling; Regimen; Regulation; Reproduction; Research Personnel; Resolution; Role; Signal Transduction; Site; Skeleton; Smell Perception; Somatomedins; Stimulus; Surface; Testing; Tissues; Veterans; Work; X-Ray Computed Tomography; bone; bone cell; bone mass; energy balance; extracellular; fatty acid metabolism; fatty acid oxidation; food consumption; glucose disposal; glucose uptake; improved; insulin secretion; insulin sensitivity; insulin signaling; macromolecule; mechanical load; member; metabolic phenotype; mouse model; novel; oxidation; postnatal; programs; public health relevance; repaired; response; skeletal; uptake

 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.

 描述（由申请人提供）： 该 Merit 项目的长期目标侧重于表征机制，区分骨骼细胞中胰岛素和 IGF-1 的作用。在上一个资助期间，我们发现了一种新的内分泌环路，胰岛素通过该环路刺激骨钙素的产生。成骨细胞反过来又充当激素，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标 mTOR 定义为将成骨细胞发育程序与燃料消耗和能量结合起来的关键检查点。我们的研究结果以及其他实验室的补充工作表明，该模型隐含着骨形成、重塑和修复是能量昂贵的过程，需要成骨细胞进行调整。该提案中描述的新的初步数据表明，成骨细胞具有氧化葡萄糖和脂肪的能力。 酸随其分化状态而变化，并受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 GLUT4 依赖性葡萄糖摄取和氧化所必需的，而 Wnt/LRP5 信号传导则调节脂肪酸 β-氧化中关键酶的活性。成骨细胞的能量底物氧化和代谢对成人骨骼中整体燃料通量的影响以及对合成代谢疗法的反应我们将检验成骨细胞和骨细胞的燃料消耗显着影响的假设。在特定目标 1 中，我们将确定作为氧化底物的葡萄糖和脂肪酸的相对需求。通过检查被设计为缺乏葡萄糖（己糖激酶 2、Hk2）和脂肪酸（肉碱）专性酶的小鼠的骨骼和代谢表型，研究成熟小鼠骨骼的代谢在特定目标 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（具体而言，我们将确定葡萄糖急性损失的影响）。 ）或脂肪酸氧化（Cpt2 KO）对负荷诱导的骨形成以及抗硬化素抗体合成代谢方案的反应虽然这些研究是在小鼠中进行的，越来越多的证据将骨钙素水平和其他成骨细胞酸度标志物与体重指数、脂肪量、胰岛素分泌和胰岛素抵抗联系起来，支持它们对人类健康的重要性。我们坚信，从我们的研究中获得的信息将增进理解。关于骨骼的代谢活动如何影响整体代谢活动的信息预计将显着改善老年退伍军人中普遍存在的相关代谢紊乱的诊断和管理以及治疗和预防。