Illuminating novel roles for the Ldb1 co-regulator in transcriptional regulation of brown adipose function

阐明 Ldb1 协同调节因子在棕色脂肪功能转录调节中的新作用

基本信息

  • 批准号:
    9759543
  • 负责人:
  • 金额:
    $ 4.36万
  • 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:
    2019-04-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Brown adipose tissue (BAT) is critical for thermogenesis and glucose/lipid homeostasis. BAT utilizes fatty acids and glucose for heat production via mitochondrial uncoupling and is thus an attractive therapeutic target for combatting obesity. Exploiting the unique energy uncoupling capacity of this tissue requires a greater understanding of underlying BAT transcriptional mechanisms. We recently reported on a transcriptional co- regulator, LIM domain binding protein 1 (Ldb1), which appears to have novel roles in BAT biology. Ldb1 acts as a dimerized scaffold allowing for the assembly of transcriptional complexes and is important for the development and function of many metabolic tissues, including the brain and pancreatic islets. However, direct roles for BAT-expressed Ldb1 have not been elucidated. I will test the hypothesis that Ldb1 directly impacts BAT function. Ldb1 deletion in isolated preadipocytes resulted in reduced Ucp1 expression upon induction to mature adipocytes. Additionally, I developed a mouse model which deleted Ldb1 in thermogenic adipocytes using a Ucp1-driven Cre recombinase, termed Ldb1ΔBAT. These knockout mice have reductions in BAT- selective mRNAs including Ucp1 and Elovl3, a result similarly observed in an X9 beige cell line lacking Ldb1. Ldb1ΔBAT mice were unable to defend body temperature during a cold challenge, suggesting thermogenic defects. We also observed glucose intolerance in Ldb1ΔBAT mice via intraperitoneal glucose challenge. To dissect the role of Ldb1 in regulating whole-body physiology, Ldb1ΔBAT will be assessed for changes in energy expenditure, respiratory quotient, thermogenesis, feeding behavior, locomotor activity, and fuel utilization using the Comprehensive Lab Animal Monitoring System. Glucose metabolism will be monitored through changes in fasting blood glucose, intraperitoneal glucose tolerance with BAT-agonist treatment, insulin tolerance test, and insulin signaling. To determine how the loss of Ldb1 affects brown adipocyte function, lipid content will be assessed via Oil Red O staining and quantitative real-time PCR for lipogenesis markers. BAT histology will determine changes to cell size and lipid content. Cellular respiration measurements will determine changes in mitochondrial function, fatty acid oxidation and glycolytic flux. To elucidate the global transcriptional role of Ldb1 in BAT gene expression, Ldb1ΔBAT mice will be crossed with a NuTRAP reporter mouse (termed Ldb1ΔNuBAT) to allow sorting of adipocyte nuclei and mRNA. These sorted fractions will be examined for global transcriptional changes via RNA-Seq, and bound targets via ChIP-Seq, with the results prioritized based on genes associated with thermogenesis, glucose and lipid metabolism, and mitochondrial function. Results from this proposal will inform future studies assessing Ldb1 roles in BAT under metabolic stresses, like high-fat diet (HFD) as well as elucidating novel Ldb1-interacting transcriptional regulators. Outcomes from this proposal and future HFD studies will enhance our understanding of transcriptional mechanisms maintaining BAT function under basal and metabolic stress conditions, which will benefit future obesity therapies.
项目总结/摘要 棕色脂肪组织(BAT)对于产热和葡萄糖/脂质稳态至关重要。BAT利用脂肪酸 和葡萄糖通过线粒体解偶联产生热量,因此是一个有吸引力的治疗靶点, 对抗肥胖症利用这种组织独特的能量解偶联能力需要更大的 理解潜在的BAT转录机制。我们最近报道了一种转录共- LIM结构域结合蛋白1(Ldb 1),它似乎在BAT生物学中具有新的作用。Ldb 1行为 作为允许转录复合物组装的二聚化支架, 许多代谢组织的发育和功能,包括脑和胰岛。然而,直接 BAT表达的Ldb 1的作用尚未阐明。我将检验Ldb 1直接影响 BAT功能。在分离的前脂肪细胞中,Ldb 1缺失导致诱导后Ucp 1表达减少, 成熟脂肪细胞此外,我开发了一种小鼠模型,在产热脂肪细胞中缺失Ldb 1 使用Ucp 1驱动的Cre重组酶,称为Ldb 1 ΔBAT。这些基因敲除小鼠的BAT- 包括Ucp 1和Elov 13的选择性mRNA,在缺乏Ldb 1的X9米色细胞系中观察到类似的结果。 Ldb 1 ΔBAT小鼠在冷攻击期间不能防御体温,这表明产热的 缺陷我们还通过腹腔内葡萄糖激发观察了Ldb 1 ΔBAT小鼠的葡萄糖耐受不良。到 剖析Ldb 1在调节全身生理学中的作用,将评估Ldb 1 ΔBAT的能量变化 消耗,呼吸商,产热,摄食行为,自发活动和燃料利用, 实验动物综合监测系统将通过以下变化监测葡萄糖代谢: 空腹血糖、BAT-激动剂治疗的腹膜内葡萄糖耐量、胰岛素耐量试验,以及 胰岛素信号为了确定Ldb 1的缺失如何影响棕色脂肪细胞的功能, 通过油红O染色和定量实时PCR评估脂肪生成标志物。BAT组织学将 确定细胞大小和脂质含量的变化。细胞呼吸测量将确定 线粒体功能、脂肪酸氧化和糖酵解通量。为了阐明的全球转录作用, Ldb 1在BAT基因表达中的作用,Ldb 1 ΔBAT小鼠将与NuTRAP报告小鼠(称为 Ldb 1 ΔNuBAT),以分选脂肪细胞核和mRNA。将检查这些排序的分数, 通过RNA-Seq检测转录变化,通过ChIP-Seq检测结合靶点,结果优先级基于 与产热、葡萄糖和脂质代谢以及线粒体功能相关的基因。结果 这一建议将为未来评估Ldb 1在代谢应激(如高脂饮食)下在BAT中作用的研究提供信息 (HFD)以及阐明新的Ldb 1相互作用的转录调节因子。本提案的成果, 未来的HFD研究将增强我们对维持BAT功能的转录机制的理解 在基础和代谢应激条件下,这将有利于未来的肥胖治疗。

项目成果

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Jessica Kepple其他文献

Jessica Kepple的其他文献

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{{ truncateString('Jessica Kepple', 18)}}的其他基金

Illuminating novel roles for the Ldb1 co-regulator in transcriptional regulation of brown adipose function
阐明 Ldb1 协同调节因子在棕色脂肪功能转录调节中的新作用
  • 批准号:
    9921202
  • 财政年份:
    2019
  • 资助金额:
    $ 4.36万
  • 项目类别:

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