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)： 这个优点项目的长期目标集中在鉴定胰岛素和IGF-1在骨骼细胞中的作用的机制上。在上一次资助期间，我们发现了一个新的内分泌环路，通过这个环路，胰岛素刺激成骨细胞产生骨钙素，骨钙素反过来作为一种激素，增加胰腺胰岛素的产生，并增强周围组织的胰岛素敏感性。其他研究将胰岛素靶mTOR定义为将成骨细胞发育计划与燃料消耗和能量代谢相结合的关键检查点。我们的发现，加上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存在调节联系。在这个模型中隐含的概念是，骨形成、重塑和修复是耗能的过程，这需要成骨细胞调整其燃料代谢和生物能量学来完成其生命周期中特定阶段的功能。这项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的能力 酸的分化状态不同，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是依赖GLUT4的葡萄糖摄取和氧化所必需的，而Wnt/LRP5信号调节脂肪酸β氧化中的关键酶的活性。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对成骨细胞的能量底物氧化和代谢对成人骨骼整体燃料通量的影响以及对合成代谢治疗的反应。我们将测试这一假设，即成骨细胞和骨细胞的燃料消耗显著影响全球燃料需求，这些细胞调整其生物能量计划以满足其生命周期中的不同需求，以及在成骨细胞能量需求增加的情况下。在具体目标1中，我们将通过检测成熟成骨细胞和骨细胞中葡萄糖(己糖激酶2，Hk2)和脂肪酸(肉毒碱棕榈酰转移酶-2，Cpt2)代谢专有酶的工程小鼠的骨骼和代谢表型，确定作为成熟小鼠骨骼氧化代谢底物的葡萄糖和脂肪酸的相对需要量。在特定目标2中，我们将确定在合成代谢活动的急性发作期间成骨细胞燃料消耗的重要性。具体地说，我们将确定急性葡萄糖丢失(Hk2KO)或脂肪酸氧化(Cpt2KO)对负荷诱导的骨形成的影响，以及对抗硬化素抗体的合成代谢方案的反应。虽然这些研究是在小鼠身上进行的，但越来越多的证据表明，骨钙素水平和成骨细胞酸度的其他标记物与体重指数、脂肪质量、胰岛素分泌和胰岛素抵抗有关，这支持了它们对人类健康的意义。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。这些信息预计将显著改善对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。