Unraveling the role of osteocytes in metabolic dysfunction associated with obesity

揭示骨细胞在肥胖相关代谢功能障碍中的作用

• 批准号: 10618056
• 负责人: Neha Dole
• 金额: $ 14.09万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618056
• 关键词: 3-Dimensional; ATAC-seq; Ablation; Affect; Behavior; Biochemical; Cells; ChIP-seq; Chromatin; Clinical; Cues; Data; Diet; Disease; Dose; Eating; Energy Metabolism; Epidemic; Epigenetic Process; Foundations; Functional disorder; Future; Glycolysis; Goals; Health; High Fat Diet; Hormones; Hyperglycemia; Hyperlipidemia; In Vitro; Intervention; Knowledge; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Molecular; Monitor; Mus; Musculoskeletal; Neurosecretory Systems; Nutrient; Nutritional; Obesity; Osteocytes; Oxidative Phosphorylation; Pathway interactions; Pattern; Pharmacology; Phenotype; Physiological; Play; Prevalence; Regulation; Research; Role; SIRT1 gene; Serum; Shapes; Signal Transduction; Skeleton; Testing; Therapeutic; Thinness; Time; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Weight Gain; Work; age related; bone; bone cell; bone fragility; diet-induced obesity; energy balance; epigenome; glucose metabolism; histone modification; improved; in vivo; insight; lipid metabolism; metabolic abnormality assessment; multiple omics; novel; outcome prediction; programs; response; success; trait; transcriptome; transcriptome sequencing

PROJECT ABSTRACT The prevalence of obesity is on the rise and a better understanding of the drivers of this epidemic is crucial. As novel insights implicate bone in regulating energy metabolism, it is crucial to understand how diseases of positive energy balance, like obesity, affect the different functions of bone. While obesity is known to impact the structural function of bone causing increased fragility, it is unclear how the metabolic function of bone is compromised in obesity. Filling this gap in our knowledge is critical for developing therapeutics that can reestablish energy metabolism while maintaining musculoskeletal health in obesity. In this proposal, we explore the effects of obesity on bone regulated energy metabolism and focus particularly on osteocytes, that constitute 95% of cells in bone. Our compelling preliminary data puts forth the premise that TGFβ signaling is a key modulator of osteocyte-intrinsic energy metabolism (cellular). Thus, we test the hypothesis that obesity impacts osteocytic TGFβ signaling that in turn contributes to deregulated systemic energy metabolism. Furthermore, our data suggest that osteocytic TGFβ signaling also coordinates the activities of epigenetic factors to shape the transcriptome of osteocytes. These epigenetic factors have previously been implicated in obesity; however, their relation to TGFβ signaling and cellular energy metabolism of osteocytes remains unexplored. Together, these findings motivate my central hypothesis, that osteocytic TGFβ signaling drives metabolic dysfunction in obesity through an epigenetic mechanism. My aims to test this hypothesis are to: 1) determine if obesity induces metabolic reprogramming in osteocytes in a TGFβ- dependent manner, 2) determine if ablation of osteocytic TGFβ rescues metabolic dysfunction in obesity, and 3) identify the function of TGFβ responsive epigenetic factors in regulating osteocyte driven energy metabolism during obesity. Using hyperglycemia and hyperlipidemia (in vitro) and DIO (diet-induced obesity, in vivo) to model obesity, we will monitor the link between osteocytic TGFβ signaling, cellular- and systemic- energy metabolism, and study its role in regulating the obesity-induced metabolic dysfunction. For combining ChIP- Seq, ATAC-Seq, and RNA-Seq approaches, we will generate a network landscape connecting epigenetic marks, modifiers, chromatin accessibility patterns, and corresponding molecular pathways that are impacted by obesity in osteocytes. In the future, this landscape of molecular and epigenetic networks will serve as a blueprint that can be used to interpret osteocyte function in metabolism in response to distinct nutrient cues. Such a blueprint will be particularly informative in devising or predicting outcomes of pharmacologic interventions and will lay the foundation for my independent research that dissects the intricacies behind the crosstalk between bone function and energy metabolism. Project Abstract

项目摘要 肥胖症的流行正在上升，对这种流行病的驱动因素有更好的理解是 至关重要的。正如新颖的见解暗示着调节能量代谢中的骨骼一样，了解如何了解如何了解 正能量平衡的疾病（如肥胖）会影响骨骼的不同功能。虽然肥胖是已知的 为了影响骨骼的结构功能导致脆弱性增加，目前尚不清楚如何如何 骨骼在肥胖症中受到损害。在我们的知识中填补这一空白对于开发可以进行的治疗至关重要 重新建立能量代谢，同时保持肥胖症中的肌肉骨骼健康。 在此提案中，我们探讨了肥胖对骨调节能量代谢的影响和重点 特别是在骨细胞上，占骨中细胞的95％。我们引人入胜的初步数据提出了 TGFβ信号传导是骨细胞 - 内膜代谢（细胞）的关键调节剂的前提。 测试肥胖症影响骨细胞TGFβ信号的假设又有助于放松管制 系统性能量代谢。此外，我们的数据表明骨细胞TGFβ信号传导也坐标 表观遗传因素的活性以塑造骨细胞的转录组。这些表观遗传因素具有 以前在肥胖症中暗示；但是，它们与TGFβ信号传导和细胞能代谢的关系 骨细胞的含量仍然出乎意料。这些发现共同激励了我的中心假设，即骨细胞 TGFβ信号传导通过表观遗传机制驱动肥胖中的代谢功能障碍。我的目的是测试这个 假设是：1）确定肥胖症是否诱导TGFβ-中骨细胞中的代谢重编程 依赖方式，2）确定骨细胞TGFβ的消融是否挽救了代谢功能障碍 肥胖和3）确定TGFβ反应性表观遗传因子在确定骨细胞中的功能 肥胖期间驱动能量代谢。 使用高血糖和高脂血症（体外）和DIO（饮食引起的肥胖症，体内） 肥胖，我们将监视骨细胞TGFβ信号传导，细胞和全身能量之间的联系 代谢，并研究其在调查肥胖诱导的代谢功能障碍中的作用。用于结合芯片 - SEQ，ATAC-SEQ和RNA-SEQ方法，我们将生成一个连接表观遗传学的网络景观 标记，修饰符，染色质可及性模式和相应的分子途径受到影响 骨细胞中的肥胖症。将来，这种分子和表观遗传网络的景观将作为一个 可用于解释代谢中骨细胞功能的蓝图，以响应不同的营养提示。 这样的蓝图将在设计或预测药理学结果方面特别有用 干预措施，并将为我的独立研究奠定基础 骨功能与能量代谢之间的串扰。 项目摘要