Bone-Adipose Interactions During Skeletal Anabolism

摘要 成骨细胞的骨形成需要大量的能量输入来推动合成、沉积和 骨基质矿化。储存在脂肪组织中的甘油三酯通过脂肪分解释放出来的脂肪酸 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 应用我们将探索骨和脂肪组织对两种刺激信号的相互作用 新骨形成：间歇性甲状旁腺激素注射和锻炼。这两种刺激都是 也与脂肪组织脂肪分解增加有关。我们的研究将确定脂肪的需求量 通过在转基因小鼠模型中检测骨形成来将酸从脂肪转移到成骨细胞 在脂肪细胞中，通过ATGL表达的消融或脂肪酸氧化的损害，脂肪细胞的脂解受到损害 成骨细胞，通过消融Cpt2的表达。我们的假设预测，对脂类代谢的操纵 这两种组织中的任何一种都会削弱对每种刺激的骨形成反应。我们的方法将告知 调节骨骼动态平衡和骨骼所需能量底物的综合生理网络 在高度合成代谢状态下形成的。此外，这些研究将使我们能够定义机制 肥胖和新陈代谢障碍，这些现在在我们社会中流行的情况，会抑制骨骼 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