Regulation of energy metabolism by an osteoblast-specific gene

成骨细胞特异性基因调节能量代谢

• 批准号: 7619474
• 负责人: Gerard Karsenty
• 金额: $ 31.1万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-05 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619474
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Age; Aging-Related Process; Atherosclerosis; Biochemical; Biochemical Genetics; Biological; Biological Process; Biology; Birth; Bone remodeling; Cell physiology; Cells; Cleaved cell; Data; Development; Diet; Disease; Embryo; Energy Metabolism; Extracellular Domain; Gene Deletion; Genes; Genetic; Hormones; Hypoglycemia; Laboratories; Leptin; Metabolic; Metabolic syndrome; Molecular; Molecular Mechanisms of Action; Mus; Mutant Strains Mice; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Osteoblasts; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Physiology; Protein Tyrosine Phosphatase; Provider; Regulation; Research Personnel; Resistance; Serum; Signal Transduction; Skeleton; Technology; Testing; Testis; Tissues; Work; adipokines; adiponectin; base; bone; bone mass; cell type; embryonic stem cell; homologous recombination; insulin secretion; insulin sensitivity; novel; phosphatase inhibitor; prevent; programs; receptor; sertoli cell; skeletal abnormality; stem

DESCRIPTION (provided by applicant): The uncovering that leptin regulated bone mass revealed the existence of a control of bone physiology by adipose tissue. Besides the emerging molecular complexity of this regulation its very existence raised a novel question. Do osteoblasts and through them bones regulate in turn expression of leptin and/or of any other adipocyte - derived hormones? To address this question we embarked in a broad-based effort to generate through E.S. cells technology multiple mouse mutant strains each of them lacking one osteoblast enriched gene. We then will analyze their energy metabolism. In the course of there studies we generated through classical and in an osteoblast-specific manner mice lacking Esp. Esp encodes a protein tyrosine phosphatase expressed in osteoblasts and in Sertoli cells of the testis. The only detectable phenotypic abnormalities of any kind one could detect in Esp-deficient mice were an hypoglycemia, an increase in insulin secretion, and an increase in adiponectin secretion resulting in an increase in insulin sensitivity. That these results were obtained in mice lacking this phosphatase only in osteoblasts establishes that bones, through a mechanism we propose to study, regulate energy metabolism. We propose in this application to use a combination of classical physiology, cell-based, molecular, biochemical and genetic approaches to begin elucidating, through Esp biology, this novel function of bones. The specific aims are: - To demonstrate that the phenotype of Espob-/- mice is due solely to an increase in adiponectin and insulin secretion. - To determine whether Espob-/- mice are resistant to diet induced obesity and type 2 diabetes. - To determine genetically whether Espob-/- mice are resistant to atherosclerosis - To determine whether or not OST-PTP acts through its extracellular domain

描述（由申请人提供）：发现瘦素调节骨量，揭示了脂肪组织对骨生理学的控制。除了这种调节机制的分子复杂性外，它的存在本身也提出了一个新的问题。成骨细胞和骨骼是否反过来调节瘦素和/或任何其他脂肪细胞衍生激素的表达？为了解决这个问题，我们开始了广泛的努力，通过E.S.细胞技术多个小鼠突变株，它们中的每一个都缺乏一个成骨细胞富集基因。然后我们将分析它们的能量代谢。在那里的研究过程中，我们通过经典的和成骨细胞特异性的方式产生的小鼠缺乏ESP。ESP编码的蛋白酪氨酸磷酸酶在成骨细胞和睾丸支持细胞中表达。在缺乏ESP的小鼠中唯一可检测到的任何类型的表型异常是低血糖、胰岛素分泌增加和脂联素分泌增加，导致胰岛素敏感性增加。这些结果是在成骨细胞中缺乏这种磷酸酶的小鼠中获得的，这表明骨骼通过我们打算研究的机制来调节能量代谢。在本申请中，我们提出使用经典生理学、基于细胞的、分子、生物化学和遗传方法的组合来通过ESP生物学开始阐明骨的这种新功能。具体目的是：-证明Espob-/-小鼠的表型仅仅是由于脂联素和胰岛素分泌增加。- 确定Espob-/-小鼠是否对饮食诱导的肥胖和2型糖尿病具有抗性。- 确定Espob-/-小鼠是否对动脉粥样硬化具有遗传抗性-确定OST-PTP是否通过其细胞外结构域发挥作用