Regulation of energy metabolism by an osteoblast-specific gene

描述(申请人提供)：瘦素调节骨量的发现揭示了通过脂肪组织控制骨生理的存在。除了这一规定正在显现的分子复杂性之外，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来源的激素的表达？为了解决这个问题，我们开始了一项广泛的努力，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丰富的基因。然后我们将分析他们的能量代谢。在这些研究过程中，我们通过经典的和成骨细胞特异性的方式产生了缺乏ESP的小鼠。ESP编码一种在成骨细胞和睾丸支持细胞中表达的蛋白质酪氨酸磷酸酶。在ESP缺陷小鼠中，唯一可检测到的任何类型的表型异常是低血糖、胰岛素分泌增加以及脂联素分泌增加导致胰岛素敏感性增加。这些结果是在只在成骨细胞中缺乏这种磷酸酶的小鼠身上获得的，这证实了骨骼通过我们建议研究的一种机制来调节能量代谢。在这项应用中，我们建议使用经典生理学、基于细胞的方法、分子、生化和遗传学方法的组合，通过ESP生物学开始阐明骨骼的这一新功能。具体目的是：-证明Espb-/-小鼠的表型完全是由于脂联素和胰岛素分泌增加所致。-确定Espb-/-小鼠是否对饮食引起的肥胖症和2型糖尿病具有抵抗力。-从遗传学上确定EspB-/-小鼠是否对动脉粥样硬化具有抵抗力--确定OST-PTP是否通过其胞外结构域发挥作用

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