Osteocalcin as a Regulator of Energy Metabolism

骨钙素作为能量代谢的调节剂

• 批准号: 8064678
• 负责人: Gerard Karsenty
• 金额: $ 48.62万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064678
• 关键词: Adipocytes; Affect; Alleles; Biological; Biology; Blood; Bone remodeling; Cell Culture Techniques; Cell Proliferation; Cells; Cues; Data; Endocrine; Energy Metabolism; Enzymes; Fatty acid glycerol esters; Feedback; Fostering; Genes; Genetic; Goals; Grant; Health; Hormones; Image; Insulin; Laboratories; Leptin; Metabolic; Metabolic syndrome; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Osteoblasts; Osteocalcin; Osteogenesis; Oxidoreductase; Pathway interactions; Phenotype; Protein Tyrosine Phosphatase; Proteins; Publishing; Regulation; Secondary to; Serum; Signaling Molecule; Skeleton; Testing; Therapeutic; Vitamin K; Wild Type Mouse; adipocyte biology; adiponectin; base; bone; bone cell; carboxylate; carboxylation; extracellular; fight against; glucose metabolism; hormone regulation; human PTPRT protein; in vivo; insulin secretion; insulin sensitivity; insulin signaling; interest; mouse model; pancreatic juice; research study; tool

DESCRIPTION (provided by applicant): The fact that an adipocyte-derived hormone like leptin regulates bone remodeling raises the project that bone cells may in turn influence adipocyte biology. While testing this hypothesis we identified a gene, Esp, encoding a tyrosine phosphatase whose osteoblast-specific deletion results in an increase in insulin and adiponectin secretion by pancreatic cells and adipocytes respectively. Looking for substrates of the Esp gene product we noted that Osteocalcin-deficient mice had a phenotype that is the mirror image of the one observed in Esp-deficient mice. Osteocalcin -/- mice display a decrease in insulin and in adiponectin secretion. Moreover, removing one allele of osteocalcin sufficed to correct the entire metabolic phenotype of the Esp -/- mice. Based on these and additional published preliminary data we have shown that osteocalcin is a hormone regulating insulin secretion and sensitivity we now intend to foster our molecular understanding of how osteocalcin regulates energy metabolism. To achieve this goal we propose the following specific aims: 1. To demonstrate that gamma carboxylase is a target of OST-PTP, the Esp gene product in vivo 2. To generate mice lacking, in osteoblasts only, the Vitamin K epoxy reductase C1, another enzyme involved in carboxylation of osteocalcin 3. To determine whether bones, through osteocalcin, are responsible of the increase in insulin secretion observed in absence of leptin 4. To define how insulin signaling in osteoblasts regulates osteocalcin expression or bioactivity. PUBLIC HEALTH RELEVANCE. Type 2 diabetes and obesity is a growing public concern. Here we identified a potential new hormone regulating glucose metabolism. This hormone may be an important therapeutic tool in the fight against the metabolic syndrome.

描述（由申请人提供）：脂肪细胞衍生的激素（如瘦素）调节骨重塑的事实提出了骨细胞可能反过来影响脂肪细胞生物学的观点。在测试这一假设时，我们发现了一个编码酪氨酸磷酸酶的基因 Esp，其成骨细胞特异性缺失会导致胰腺细胞和脂肪细胞分别分泌胰岛素和脂联素增加。在寻找 Esp 基因产物的底物时，我们注意到骨钙素缺陷小鼠的表型与 Esp 缺陷小鼠中观察到的表型是镜像的。骨钙素-/-小鼠表现出胰岛素和脂联素分泌减少。此外，去除骨钙素的一个等位基因足以纠正Esp -/- 小鼠的整个代谢表型。基于这些和其他已发表的初步数据，我们已经表明骨钙素是一种调节胰岛素分泌和敏感性的激素，我们现在打算促进对骨钙素如何调节能量代谢的分子理解。为了实现这一目标，我们提出以下具体目标： 1. 证明 γ 羧化酶是 OST-PTP（体内 Esp 基因产物）的靶标 2. 产生仅在成骨细胞中缺乏维生素 K 环氧还原酶 C1（另一种参与骨钙素羧化的酶）的小鼠 3. 确定骨骼是否通过骨钙素负责 在缺乏瘦素的情况下观察到的胰岛素分泌增加 4. 确定成骨细胞中的胰岛素信号如何调节骨钙蛋白表达或生物活性。公共卫生相关性。 2 型糖尿病和肥胖症日益受到公众关注。在这里，我们发现了一种潜在的调节葡萄糖代谢的新激素。这种激素可能是对抗代谢综合征的重要治疗工具。