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: 10670979
• 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/10670979
• 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; Equilibrium; 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; 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; multiple omics; novel; outcome prediction; pharmacologic; 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，对这一流行病的驱动因素有更好的了解 至关重要。随着新的洞察力暗示骨骼在调节能量代谢中的作用，了解骨骼是如何 正能量平衡疾病，如肥胖，会影响骨骼的不同功能。虽然肥胖是已知的 影响骨骼的结构功能导致骨脆性增加，目前尚不清楚 肥胖会损害骨骼。填补我们知识中的这一空白对于开发能够 在保持肥胖患者肌肉骨骼健康的同时，重建能量代谢。 在这个方案中，我们探讨了肥胖对骨调节能量代谢和焦点的影响。 尤其是骨细胞，它占骨骼细胞的95%。我们令人信服的初步数据表明 前提是转化生长因子β信号是骨细胞内在能量代谢(细胞)的关键调节器。因此，我们 测试肥胖影响骨细胞转化生长因子β信号进而促进去调节的假设 全身能量代谢。此外，我们的数据表明，骨细胞转化生长因子β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，它们与转化生长因子β信号和细胞能量代谢的关系 关于骨细胞的研究仍未被发现。综上所述，这些发现激发了我的中心假设，即骨细胞 转化生长因子β信号通过表观遗传机制驱动肥胖的代谢功能障碍。我的目标是测试这一点 假说是：1)确定肥胖是否诱导转化生长因子β中骨细胞的代谢重编程。 依赖方式，2)确定去除成骨细胞转化生长因子β是否能挽救脑内代谢功能障碍 3)确定转化生长因子β反应性表观遗传因子在骨细胞调控中的作用 在肥胖期间驱动能量新陈代谢。 用高血糖、高脂血症(体外)和DIO(饮食诱导肥胖，体内)建立动物模型 肥胖，我们将监测成骨细胞转化生长因子β信号与细胞和全身能量之间的联系 研究其对肥胖所致代谢紊乱的调节作用。将芯片组合在一起- 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 影响标记、修饰物、染色质可及性模式和相应的分子途径 骨细胞肥胖症。在未来，这种分子和表观遗传网络的格局将成为 可用于解释骨细胞在新陈代谢中的功能的蓝图，以响应不同的营养提示。 这样的蓝图在设计或预测药理学结果时将特别有用。 干预措施，并将为我的独立研究奠定基础，该研究剖析了 骨骼功能和能量代谢之间的串扰。 项目摘要