Adipsin from bone marrow fat as a regulator of bone remodeling

来自骨髓脂肪的脂肪素作为骨重塑的调节剂

• 批准号: 10064759
• 负责人: NICOLE AARON
• 金额: $ 4.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064759
• 关键词: Address; Adipocytes; Adipose tissue; Adverse effects; Affect; Age-Related Bone Loss; Alternative Complement Pathway; Antibodies; Arginine; Attenuated; Biological Assay; Bone Diseases; Bone Marrow; Bone remodeling; Cardiovascular Diseases; Cell Culture Techniques; Cells; Clinical; Complement 3; Complement Factor D; Deacetylation; Deterioration; Development; Endocrine; Environment; Equilibrium; Fatty acid glycerol esters; Fracture; Health; Heart; Hematopoietic; Homeostasis; Hormones; Impairment; Inflammation; Insulin Resistance; Knockout Mice; Laboratories; Lead; Lipids; Liver; Marrow; Mature Bone; Mediating; Mediator of activation protein; Mesenchymal Differentiation; Mesenchymal Stem Cells; Metabolic; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Organ; Osteoblasts; Osteogenesis; Osteoporosis; Outcome; Oxidative Stress; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Play; Post-Translational Protein Processing; Prevalence; Process; Proteins; Regulation; Research Design; Research Personnel; Risk; Role; Signal Transduction; Testing; Visceral; adipocyte biology; adipokines; bone; bone cell; bone health; bone loss; complement system; diabetes mellitus therapy; geographic atrophy; insulin sensitizing drugs; lipid biosynthesis; loss of function; mouse model; new therapeutic target; novel; osteogenic; protective effect; response; skeletal; stem cell differentiation; stem cells; transcription factor

PROJECT SUMMARY Current studies aim to understand the deleterious effects of adiposity on visceral organs such as the heart and liver. Less is understood about the effect of adipose tissue on the development and regulation of bone. Obesity is highly correlated with conditions of bone loss, including osteoporosis. Additionally, the loss of bone is associated with an increase in adiposity within the bone marrow niche. These bone marrow adipocytes (BMA) originate from the same progenitor cell as osteoblasts, the precursors to mature bone-forming cells. Activation of PPARg, an important transcription factor found primarily in adipocytes, drives adipogenesis at the expense of osteoblastogenesis. PPARg activation is also associated with reduced inflammation and the repartitioning of lipids away from organs ill-equipped to cope with a lipotoxic environment, making it a good target for insulin- sensitizing drugs known as Thiazolidines (TZD). Unfortunately, clinical use of TZDs is associated with increased risk for bone fractures due to impaired skeletal integrity. As such, maintaining skeletal health in obese patients, particularly those receiving TZD treatment, has become a critical challenge. Previously identified post-translational modifications (PTM) of PPARg have dissociated the insulin-sensitizing effects of TZD treatment from the negative outcomes. The constitutive deacetylation of Lys268 and Lys293 by conversion to Arginine residues in a mouse model has been shown to ameliorate bone loss and reduce marrow adiposity. To further elucidate the mechanism through which this PPARg PTM protects bone deterioration, the investigator proposes to uncover the functional role that bone marrow adipocytes play within the hematopoietic niche, including the extent to which BMA-derived adipokines contribute to skeletal remodeling. Specifically, she plans to identify adipsin as a key adipokine that is altered in response to PPARg deacetylation and is a potential modulator of the balance between marrow adipocytes and bone cells. In Aim 1 the investigator will identify adipsin as a mediator of the bone protective effect caused by PPARg deacetylation. Furthermore, she plans to elucidate the mechanism through which adipsin mediates the crosstalk between bone and bone marrow adipocytes in Aim 2 by assessing the role of adipsin released from peripheral and bone marrow adipose tissue using primary cells and an adipsin knockout mouse model. In addition to its potential role in bone regulation, adipsin is known to be involved in the alternative pathway of the complement system. In Aim 3 she plans to establish the role of the complement system in bone homeostasis through adipsin. Ultimately, this study will identify the molecular mechanism by which PPARg deacetylation selectively protects bone homeostasis. The identification of adipsin as a novel regulator of skeletal remodeling processes will advance the field of adipocyte biology by elucidating a novel adipokine to connect fat and bone.

项目摘要 当前的研究旨在了解肥胖对内脏器官（例如心脏和心脏）的有害影响 肝。关于脂肪组织对骨骼发育和调节的影响的理解较少。肥胖 与骨质流失的条件高度相关，包括骨质疏松症。此外，骨骼的损失是 与骨髓小裂内肥胖的增加有关。这些骨髓脂肪细胞（BMA） 起源于与成骨细胞相同的祖细胞，这是成熟骨形成细胞的前体。激活 PPARG是主要在脂肪细胞中发现的重要转录因子，以促进脂肪形成为代价 成骨细胞生成。 PPARG激活还与炎症减少和重新分配有关 脂质远离装备不足的器官以应对脂肪毒性环境，使其成为胰岛素的良好靶 敏化药物称为噻唑烷类（TZD）。不幸的是，TZD的临床使用与增加有关 由于骨骼完整性受损而导致的骨折风险。因此，维持肥胖患者的骨骼健康， 特别是那些接受TZD治疗的人已成为一个至关重要的挑战。 先前确定的PPARG翻译后修饰（PTM）已解离胰岛素敏化 TZD治疗对负面结果的影响。 lys268和lys293的本构脱乙酰基化 在小鼠模型中转化为精氨酸残基已显示可改善骨质流失并减少骨髓 肥胖。为了进一步阐明该PPARG PTM保护骨变质的机制， 研究者建议揭示造血性骨髓脂肪细胞发挥的功能作用 利基，包括BMA衍生的脂肪因子有助于骨骼重塑的程度。特别是她 计划将脂蛋白识别为对PPARG脱乙酰化的响应改变的关键脂肪因子，并且潜在 骨髓脂肪细胞和骨细胞之间平衡的调节剂。 在AIM 1中，研究者将识别脂肪素是PPARG引起的骨骼保护作用的介体 脱乙酰化。此外，她计划阐明adipsin介导串扰的机制 AIM 2中的骨髓脂肪细胞和骨髓脂肪细胞之间通过评估脂肪的作用 使用原代细胞和脂肪敲除小鼠模型和骨髓脂肪组织。除了它的 已知脂蛋白在骨调节中的潜在作用与补体的替代途径有关 系统。在AIM 3中，她计划通过adipsin在骨体内平衡中建立补体系统的作用。 最终，这项研究将确定PPARG脱乙酰化选择性保护的分子机制 骨体内平衡。将脂肪素鉴定为骨骼重塑过程的新型调节剂 通过阐明一种新型脂肪因子来连接脂肪和骨骼，推进脂肪细胞生物学领域。