Regulation of energy metabolism by an osteoblast-specific gene

描述（由申请人提供）：瘦素调节骨量的发现揭示了脂肪组织对骨生理的控制。除了这种调控的分子复杂性之外，它的存在本身就提出了一个新的问题。成骨细胞和通过它们的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.细胞技术产生多个小鼠突变株，每个突变株都缺乏一个成骨细胞富集基因。然后我们会分析他们的能量代谢。在这些研究过程中，我们通过传统的和成骨细胞特异性的方式产生了缺乏Esp的小鼠。Esp编码一种蛋白酪氨酸磷酸酶，在成骨细胞和睾丸的支持细胞中表达。在缺乏esp的小鼠中，唯一可检测到的表型异常是低血糖，胰岛素分泌增加，脂联素分泌增加，导致胰岛素敏感性增加。这些结果仅在成骨细胞中缺乏这种磷酸酶的小鼠中获得，这表明骨骼通过我们拟研究的机制调节能量代谢。在这个应用中，我们建议结合经典生理学、细胞基础、分子、生化和遗传方法，通过Esp生物学来开始阐明骨骼的这种新功能。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的增加。-确定Espob-/-小鼠是否对饮食性肥胖和2型糖尿病具有抗性。-从遗传学角度确定Espob-/-小鼠是否对动脉粥样硬化具有抗性-确定OST-PTP是否通过其细胞外结构域起作用

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