Bone-Adipose Interactions During Skeletal Anabolism

摘要 通过成骨细胞的骨形成需要大量的能量输入来为骨合成、沉积和降解提供燃料。 骨基质矿化。储存在脂肪组织中的甘油三酯的脂解释放的脂肪酸是 一种丰富的能量来源，用于为许多组织的能量密集型功能提供燃料。在这 我们将探讨骨和脂肪组织的相互作用，以响应两个信号，刺激 新骨形成：间歇性甲状旁腺激素给药和运动。这两种刺激都是 也与脂肪组织脂解的增加有关。我们的研究将确定对脂肪的需求 通过检查转基因小鼠模型中的骨形成， 其脂肪分解在脂肪细胞中受损，通过Atgl表达的消融或脂肪酸氧化受损， 成骨细胞，通过消融Cpt 2表达。我们的假设预测，操纵脂质代谢 在任一组织中的损伤将损害对每种刺激的骨形成反应。我们的方法将告知 调节骨骼稳态和骨所需能量底物的整合生理网络 在高度的安东拉状态下形成。此外，这些研究将使我们能够确定机制， 肥胖和代谢功能障碍，这些现在在我们社会中流行的疾病， 形成

Abstract Bone formation by osteoblasts requires significant energy input to fuel the synthesis, deposition, and mineralization of bone matrix. Fatty acids liberated by the lipolysis of triglycerides stored in adipose tissue are a rich source of energy that is used to fuel the energy-intensive functions of a number of tissues. In this application we will explore the interaction of bone and adipose tissue in response to two signals that stimulate new bone formation: intermittent parathyroid hormone administration and exercise. Both of these stimuli are also associated with increases in adipose tissue lipolysis. Our studies will determine the requirement for fatty acids to be transferred from adipose to osteoblasts by examining bone formation in transgenic mouse models in which lipolysis is impaired in adipocytes, via ablation of Atgl expression or fatty acid oxidation is impaired in osteoblasts, via the ablation of Cpt2 expression. Our hypothesis predicts that manipulation of lipid metabolism in either tissue will impair the bone formation response to each stimulus. Our approach will inform on the integrative physiologic networks that regulate skeletal homeostasis and the energy substrates required for bone formation during states of heighted anabolism. Additionally, these studies will enable us to define mechanisms by which obesity and metabolic dysfunction, conditions which are now epidemic in our society, inhibit bone formation