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.

项目概要 目前的研究旨在了解肥胖对心脏等内脏器官的有害影响 肝。人们对脂肪组织对骨骼发育和调节的影响知之甚少。肥胖 与骨质流失状况高度相关，包括骨质疏松症。另外，骨质流失是 与骨髓生态位内肥胖的增加有关。这些骨髓脂肪细胞（BMA） 与成骨细胞源自相同的祖细胞，成骨细胞是成熟骨形成细胞的前体。激活 PPARg 是一种主要存在于脂肪细胞中的重要转录因子，它以牺牲 成骨细胞发生。 PPARg 激活还与炎症减轻和细胞重新分配相关。 脂质远离那些无力应对脂毒性环境的器官，使其成为胰岛素的良好目标 称为噻唑烷（TZD）的致敏药物。不幸的是，TZD 的临床使用与增加 由于骨骼完整性受损而导致骨折的风险。因此，保持肥胖患者的骨骼健康， 特别是那些接受 TZD 治疗的患者，已成为一项严峻的挑战。 先前鉴定的 PPARg 翻译后修饰 (PTM) 已解离胰岛素增敏作用 TZD 治疗的负面结果。 Lys268 和 Lys293 的组成型脱乙酰化 在小鼠模型中转化为精氨酸残基已被证明可以改善骨质流失并减少骨髓 肥胖。为了进一步阐明 PPARg PTM 保护骨质退化的机制， 研究人员建议揭示骨髓脂肪细胞在造血系统中发挥的功能作用 利基，包括 BMA 衍生的脂肪因子对骨骼重塑的贡献程度。具体来说，她 计划将 adipsin 确定为一种关键的脂肪因子，它会响应 PPARg 脱乙酰化而发生改变，并且是一种潜在的脂肪因子。 骨髓脂肪细胞和骨细胞之间平衡的调节剂。 在目标 1 中，研究者将确定 adipsin 作为 PPARg 引起的骨保护作用的介质 脱乙酰化。此外，她计划阐明adipsin介导串扰的机制 通过评估外周释放的脂肪素的作用，在目标 2 中评估骨和骨髓脂肪细胞之间的关系 和使用原代细胞和脂肪酶敲除小鼠模型的骨髓脂肪组织。除了它的 在骨调节中的潜在作用，adipsin 已知参与补体的替代途径 系统。在目标 3 中，她计划通过 Adipsin 确定补体系统在骨稳态中的作用。 最终，本研究将确定 PPARg 脱乙酰选择性保护的分子机制 骨稳态。 Adipsin 作为骨骼重塑过程的新型调节剂的鉴定将 通过阐明一种连接脂肪和骨骼的新型脂肪因子，推进了脂肪细胞生物学领域。