Epigenetic regulation of brown fat thermogenesis by the histone demethylase KDM6A

组蛋白去甲基化酶 KDM6A 对棕色脂肪产热的表观遗传调控

基本信息

  • 批准号:
    10166835
  • 负责人:
  • 金额:
    $ 41.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-07-17 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

Obesity is a disorder of energy homeostasis due to energy intake over energy expenditure. Adaptive thermogenesis, in which brown adipose tissue (BAT) functions to dissipate energy as heat, is an integral part of overall energy expenditure. Obesity is a complex disease resulting from gene and environment interactions. One of the mechanisms that environmental factors such as diets affect gene expression patterns involves their capacity to reprogram the epigenome. Evidence converges to suggest that epigenetic events, including histone methylation, figure prominently in the development of obesity. Lysine (K) specific demethylase 6A (KDM6A) is a histone demethylase that preferentially demethylates tri-methylated histone lysine 27 (H3K27me3) and therefore relieves its ability to silence the genes, leading to activation of the gene transcription. Our published and preliminary data suggest that KDM6A is important in regulating brown fat thermogenic program, energy metabolism and diet-induced obesity (DIO), and that KDM6A overexpression increases the expression and secretion of a BAT-derived neurotrophic factor neurotrophin 3 (NT3), which enhances sympathetic nervous system (SNS) innervation into adipose tissue. Therefore, we hypothesize that KDM6A plays an important role in regulating brown fat thermogenesis, energy metabolism and obesity, and that KDM6A-stimulated NT3, a BAT-derived neurotropic factor, promotes brown/beige cell thermogenesis via enhanced SNS innervation. Aim 1 will determine the role of KDM6A in cold-induced thermogenesis, energy metabolism and diet-induced obesity in genetic models. We will use brown fat KDM6A deficient or overexpressing mice (named AKO and AOE mice, respectively) to determine whether specific deletion of KDM6A in brown fat impairs brown fat thermogenesis during cold exposure and promotes diet-induced obesity, whereas specific overexpression of KDM6A in brown fat does the opposite. O-GlcNAcylation has emerged as a key nutrient sensor that regulates cellular metabolic pathways in response to overnutritional cues (e.g. excess glucose and fatty acids). We will determine whether KDM6A O-GlcNAcylation by excess nutrients (glucose and fatty acids) decreases its ability to demethylate H3K27me3 at the thermogenic gene promoters, thereby compromising diet-induced thermogenesis. Aim 2 will investigate the role of KDMK6A-stimulated NT3, a brown fat-derived neurotropic factor, in regulating adaptive thermogenesis, energy metabolism and diet-induced obesity, via sympathetic innervation into adipose tissue. We have generated mice with adipocyte-specific overexpression of NT3. We will determine 1) whether adipose overexpression of NT3 promotes cold-induced thermogenesis and prevents diet-induced obesity; 2) whether NT3 stimulates SNS innervation into adipose tissue and sympathetic neuron axonal growth via activating its receptor tropomyosin receptor kinase C (TRKC); 3) whether or to what extent NT3 mediates the effect of KDM6A in promoting brown/beige cell thermogenesis and preventing DIO. Completion of this project could help guide the development of KDM6A and NT3 as new therapeutic targets in the treatment of obesity.
肥胖是由于能量摄入超过能量消耗而导致的能量稳态紊乱。适应性产热,其中棕色脂肪组织(BAT)的功能,以散热的能量,是整体能量消耗的一个组成部分。肥胖是一种基因与环境相互作用的复杂疾病。饮食等环境因素影响基因表达模式的机制之一涉及它们重编程表观基因组的能力。证据表明,表观遗传事件,包括组蛋白甲基化,在肥胖的发展中起着重要作用。赖氨酸(K)特异性脱甲基酶6A(KDM 6A)是一种组蛋白脱甲基酶,其优先使三甲基化的组蛋白赖氨酸27(H3 K27 me 3)脱甲基,因此减轻其沉默基因的能力,导致基因转录的激活。我们发表的和初步的数据表明,KDM 6A在调节棕色脂肪产热程序,能量代谢和饮食诱导的肥胖症(DIO)中是重要的,并且KDM 6A过表达增加BAT衍生的神经营养因子神经营养因子3(NT 3)的表达和分泌,其增强交感神经系统(SNS)神经支配脂肪组织。因此,我们假设KDM 6A在调节棕色脂肪产热、能量代谢和肥胖中起重要作用,并且KDM 6A刺激的NT 3(BAT衍生的神经营养因子)通过增强SNS神经支配促进棕色/米色细胞产热。目的1在遗传模型中确定KDM 6A在冷诱导的产热、能量代谢和饮食诱导的肥胖中的作用。我们将使用棕色脂肪KDM 6A缺陷或过表达小鼠(分别命名为AKO和AOE小鼠)来确定棕色脂肪中KDM 6A的特异性缺失是否会在冷暴露期间损害棕色脂肪产热并促进饮食诱导的肥胖,而棕色脂肪中KDM 6A的特异性过表达则相反。O-GlcNAc酰化已成为一种关键的营养传感器,可调节细胞代谢途径,以响应营养过度的提示(例如过量的葡萄糖和脂肪酸)。我们将确定是否KDM 6A O-GlcNAc酰化过量的营养物质(葡萄糖和脂肪酸)降低其能力去甲基化H3 K27 me 3在产热基因启动子,从而损害饮食诱导的产热。目的2研究KDMK 6A刺激的NT 3(一种棕色脂肪源性神经营养因子)通过交感神经支配进入脂肪组织,在调节适应性产热、能量代谢和饮食诱导的肥胖中的作用。我们已经产生了脂肪细胞特异性过表达NT 3的小鼠。我们将确定1)NT 3的脂肪过表达是否促进冷诱导的产热并防止饮食诱导的肥胖; 2)NT 3是否通过激活其受体原肌球蛋白受体激酶C(TRKC)刺激SNS神经支配进入脂肪组织和交感神经元轴突生长; 3)NT 3是否或在多大程度上介导KDM 6A在促进棕色/米色细胞产热和防止DIO中的作用。该项目的完成可能有助于指导KDM 6A和NT 3作为肥胖治疗新靶点的开发。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Hang Shi其他文献

Hang Shi的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Hang Shi', 18)}}的其他基金

HDAC1 as a nutrient sensor in the development and progression of NAFLD
HDAC1 作为 NAFLD 发生和进展中的营养传感器
  • 批准号:
    10633180
  • 财政年份:
    2022
  • 资助金额:
    $ 41.98万
  • 项目类别:
HDAC1 as a nutrient sensor in the development and progression of NAFLD
HDAC1 作为 NAFLD 发生和进展中的营养传感器
  • 批准号:
    10469203
  • 财政年份:
    2022
  • 资助金额:
    $ 41.98万
  • 项目类别:
Epigenetic regulation of brown fat thermogenesis by the histone demethylase KDM6A
组蛋白去甲基化酶 KDM6A 对棕色脂肪产热的表观遗传调控
  • 批准号:
    10418682
  • 财政年份:
    2019
  • 资助金额:
    $ 41.98万
  • 项目类别:
Epigenetic regulation of brown fat thermogenesis by the histone demethylase KDM6A
组蛋白去甲基化酶 KDM6A 对棕色脂肪产热的表观遗传调控
  • 批准号:
    9979853
  • 财政年份:
    2019
  • 资助金额:
    $ 41.98万
  • 项目类别:
HDAC1 regulates thermogenic program via H3K27 deacetylation
HDAC1 通过 H3K27 脱乙酰化调节生热程序
  • 批准号:
    10180949
  • 财政年份:
    2018
  • 资助金额:
    $ 41.98万
  • 项目类别:
HDAC1 regulates thermogenic program via H3K27 deacetylation
HDAC1 通过 H3K27 脱乙酰化调节生热程序
  • 批准号:
    9978048
  • 财政年份:
    2018
  • 资助金额:
    $ 41.98万
  • 项目类别:
Epigenetic programming of beta-klotho in non-alcoholic fatty liver disease
β-klotho 在非酒精性脂肪肝病中的表观遗传编程
  • 批准号:
    9493612
  • 财政年份:
    2018
  • 资助金额:
    $ 41.98万
  • 项目类别:
Epigenetic programming of beta-klotho in non-alcoholic fatty liver disease
β-klotho 在非酒精性脂肪肝病中的表观遗传编程
  • 批准号:
    9918345
  • 财政年份:
    2018
  • 资助金额:
    $ 41.98万
  • 项目类别:
The AMP-Activated Protein Kinase (AMPK) Antagonizes Inflammation Through SIRT1
AMP 激活蛋白激酶 (AMPK) 通过 SIRT1 对抗炎症
  • 批准号:
    8101869
  • 财政年份:
    2009
  • 资助金额:
    $ 41.98万
  • 项目类别:
The AMP-Activated Protein Kinase (AMPK) Antagonizes Inflammation Through SIRT1
AMP 激活蛋白激酶 (AMPK) 通过 SIRT1 对抗炎症
  • 批准号:
    8495455
  • 财政年份:
    2009
  • 资助金额:
    $ 41.98万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.98万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了