Bone-Adipose Interactions During Skeletal Anabolism

骨骼合成代谢过程中骨-脂肪相互作用

• 批准号: 10590611
• 负责人: Ryan C Riddle
• 金额: $ 33.99万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590611
• 关键词: Ablation; Acute; Address; Adipocytes; Adipose tissue; Adrenergic Agents; Anabolism; Architecture; Biochemistry; Biology; Bone Formation Inhibition; Bone Matrix; Bone Tissue; C57BL/6 Mouse; Carbon; Carnitine Palmitoyltransferase I; Cell Line; Cell Lineage; Citric Acid Cycle; Collaborations; Data; Deposition; Development; Distant; Energy-Generating Resources; Enzymes; Epidemic; Exercise; Exercise Physiology; Exposure to; Fatty Acids; Gene Expression; Genetic; Height; Homeostasis; Hormones; Impairment; In Vitro; Interleukin-6; Label; Laboratories; Lipase; Lipolysis; LoxP-flanked allele; Manuscripts; Mass Spectrum Analysis; Mediating; Metabolic dysfunction; Mitochondria; Modification; Monitor; Mus; Obesity; Osteoblasts; Osteogenesis; Osteopenia; PTH gene; Palmitates; Performance; Physiologic calcification; Physiological; Physiology; Productivity; Running; Signal Transduction; Societies; Stimulus; Therapeutic; Therapeutic Effect; Tissues; Training; Transgenic Mice; Triglycerides; Work; bone; bone mass; bone strength; extracellular; fatty acid oxidation; in vivo; lipid metabolism; long chain fatty acid; microCT; mouse model; novel strategies; osteoblast differentiation; osteogenic; oxidation; receptor; response; skeletal; skeletal stem cell; treadmill; uptake

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

抽象的 成骨细胞的骨形成需要大量的能量输入来促进合成、沉积和形成 骨基质矿化。储存在脂肪组织中的甘油三酯脂解后释放的脂肪酸是 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。在这个 在应用程序中，我们将探索骨骼和脂肪组织响应两个刺激信号的相互作用 新骨形成：间歇性甲状旁腺激素给药和锻炼。这两种刺激都是 还与脂肪组织脂解作用的增加有关。我们的研究将确定脂肪的需求 通过检查转基因小鼠模型中的骨形成，将酸从脂肪转移到成骨细胞 通过 Atgl 表达的消融或脂肪酸氧化的损害，脂肪细胞中的脂解作用受到损害 成骨细胞，通过消除 Cpt2 表达。我们的假设预测脂质代谢的操纵 任何一种组织都会损害骨形成对每种刺激的反应。我们的方法将告知 调节骨骼稳态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。此外，这些研究将使我们能够定义机制 肥胖和代谢功能障碍（目前在我们社会中流行的疾病）会抑制骨骼 形成

项目成果

Mitochondrial β-oxidation of adipose-derived fatty acids by osteoblasts fuels parathyroid hormone-induced bone formation.

• DOI: 10.1172/jci.insight.165604
• 发表时间: 2023-03-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Alekos, Nathalie S. .;Kushwaha, Priyanka;Kim, Soohyun P. .;Li, Zhu;Abood, Abdullah;Dirckx, Naomi;Aja, Susan;Kodama, Joe;Garcia-Diaz, Jean G. .;Otsuru, Satoru;Rendina-Ruedy, Elizabeth;Wolfgang, Michael J. .;Riddle, Ryan C. .
• 通讯作者: Riddle, Ryan C. .