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）： 该优点项目的长期目标集中在表征机制，该机制区分了胰岛素和IGF-1在骨骼细胞中的作用。在最后的资金期间，我们确定了一种新型的内分泌环路，通过该环蛋白通过成骨细胞刺激骨钙素的产生，而成骨细胞又可以用作刺痛来增加胰腺胰岛素的产生并增强外周组织中胰岛素敏感性。其他研究将胰岛素靶标MTOR定义为关键检查点，将成骨细胞的发育计划与燃料消耗和能量代谢相结合。我们的发现以及其他实验室的完整工作，提出了成骨细胞与全球能量稳态之间的调节联系。该模型中隐含的是这样的观念，即骨形成，重塑和修复是能量昂贵的过程，需要成骨细胞来调整其燃料代谢和生物能学以在其生命周期内完成特定于阶段的功能。本提案中描述的新初步数据表明，成骨细胞对氧化物葡萄糖和脂肪的能力 酸随其分化状态而变化，并由不同的发育信号控制。 因此，对于GLUT4依赖性葡萄糖摄取和氧化需要胰岛素接收器信号传导，而Wnt/LRP5信号传导调节脂肪酸β-氧化中关键酶的活性。在该项目中，我们将使用新的遗传小鼠模型来确定成骨细胞对成年骨中全球燃料通量以及对合成代谢疗法的响应的能量底物氧化和代谢的影响。我们将检验以下假设：成骨细胞和骨细胞的燃料消耗会显着影响全球燃料的需求，并且这些细胞调整其生物能源计划以在其寿命范围内以及在成骨细胞能量需求中的环境中满足不同需求。在特定的目标1中，我们将通过检查成熟小鼠骨中氧化代谢的底物的相对需求，通过检查葡萄糖（Hexokinase 2，HK2，HK2）和脂肪酸（carnitine Palitoylmitoylmitoylmitoylmitoylmitoylmitoylmitoylmitoylmitanylastransansctfransansantanctransransansctftransransansansant222）的小鼠的骨骼和代谢表型，通过研究成熟小鼠骨骼中的氧化代谢底物。成骨细胞和骨细胞。在特定的目标2中，我们将确定成骨细胞燃料消耗在合成代谢活性急性发作中的重要性。具体而言，我们将确定葡萄糖（HK2 KO）或脂肪酸氧化（CPT2 KO）对载荷诱导的骨形成的影响，并响应抗固定蛋白抗体的合成代谢方案。尽管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，这些证据与骨钙素水平和其他标志物有关成骨细胞酸度与体重指数，脂肪质量，胰岛素分泌和胰岛素抵抗的标志。我们首先认为，从我们的研究中获得的信息将提高人们对骨架的代谢活动如何影响全球代谢活性的理解。预计此类信息将显着改善老年退伍军人普遍存在的相关代谢灾害的诊断和治疗以及预防。