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 肥胖症的流行率正在上升，更好地了解这种流行病的驱动因素是 至关重要的.由于新的见解涉及骨骼调节能量代谢，因此了解骨骼如何调节能量代谢至关重要。 正能量平衡的疾病，如肥胖，影响骨骼的不同功能。虽然肥胖是众所周知的， 影响骨骼的结构功能，导致脆性增加，目前还不清楚骨骼的代谢功能如何影响骨骼的结构功能， 肥胖会损害骨骼。填补我们知识中的这一空白对于开发治疗方法至关重要， 重建能量代谢，同时维持肥胖症患者的肌肉骨骼健康。 在这项建议中，我们探讨了肥胖对骨调节能量代谢的影响， 尤其是骨细胞，占骨细胞的95%。我们令人信服的初步数据表明， 前提是TGFβ信号传导是骨细胞内在能量代谢（细胞）的关键调节剂。因此我们 测试肥胖影响骨细胞TGFβ信号传导的假设，这反过来又有助于放松调节， 全身能量代谢此外，我们的数据表明，骨细胞TGFβ信号也协调 表观遗传因子塑造骨细胞转录组的活动。这些表观遗传因素 以前与肥胖有关;然而，它们与TGFβ信号传导和细胞能量代谢的关系 骨细胞的数量还未被探索。总之，这些发现激发了我的核心假设，即骨细胞 TGFβ信号通过表观遗传机制驱动肥胖症中的代谢功能障碍。我的目标是测试这个 假设是：1）确定肥胖是否诱导TGFβ-β受体中骨细胞的代谢重编程， 2）确定骨细胞TGFβ的消融是否能挽救代谢功能障碍， 3）研究TGFβ反应性表观遗传因子在骨细胞分化中的作用 在肥胖时驱动能量代谢。 采用高血糖、高脂血症（体外）和饮食诱导肥胖（DIO，体内）模型 肥胖，我们将监测骨细胞TGFβ信号，细胞和系统能量之间的联系 研究其对肥胖引起的代谢紊乱的调节作用。为了结合ChIP- 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、染色质可及性模式以及受影响的相应分子途径 肥胖的骨细胞。在未来，这种分子和表观遗传网络的景观将成为一种 蓝图，可用于解释骨细胞功能的代谢反应不同的营养线索。 这样的蓝图在设计或预测药理学结果方面特别有用 干预措施，并将奠定基础，我的独立研究，剖析背后的错综复杂的 骨功能和能量代谢之间的相互作用。 项目摘要