Osteocalcin as a regulator of energy metabolism

描述(申请人提供)：事实上，一种脂肪细胞衍生的激素，如瘦素，可以调节骨骼重塑，这增加了骨细胞可能反过来影响脂肪细胞生物学的项目。在验证这一假设时，我们发现了一种编码酪氨酸磷酸酶的基因ESP，该基因的成骨细胞特异性缺失会导致胰腺细胞和脂肪细胞分别增加胰岛素和脂联素的分泌。在寻找ESP基因产物的底物时，我们注意到骨钙素缺乏的小鼠具有与ESP缺乏小鼠相同的表型。骨钙素基因突变的小鼠表现出胰岛素和脂联素分泌的减少。此外，去除骨钙素的一个等位基因就足以纠正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，我们已经证明骨钙素是一种调节胰岛素分泌和敏感性的激素，我们现在打算促进我们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，我们提出了以下具体目标：1.为了证明伽玛羧化酶是体内ESP基因产物OST-PTP的靶标2.为了产生只在成骨细胞中缺乏维生素K环氧还原酶C1的小鼠，这是另一种与骨钙素羧化有关的酶3.为了确定在没有瘦素的情况下骨骼是否通过骨钙素导致胰岛素分泌增加4.确定成骨细胞中的胰岛素信号如何调节骨钙素的表达或生物活性与公共卫生相关。2型糖尿病和肥胖症是公众日益关注的问题。在这里，我们确定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。

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.