Adipocyte to neuron signaling in thermogenic programming of white adipose tissue

白色脂肪组织产热编程中的脂肪细胞至神经元信号传导

基本信息

项目摘要

Abstract The overarching long term goal of our laboratory is to understand and exploit how adipose tissues exert powerful control over whole body glucose tolerance and insulin sensitivity. Small amounts of mouse brown (BAT) or human “Beige” adipocytes transplanted into recipient mice can improve glucose homeostasis, highlighting the importance of understanding mechanisms of adipose browning. Based on the knowledge that intermediates of the de novo lipogenesis (DNL) pathway display potent signaling functions (e.g., Acetyl CoA as substrate for histone acetylation, transcriptional regulation) and that adipocyte DNL is highly regulated by obesity, fasting, cold exposure, and exercise, we hypothesize that adipocyte DNL is a major regulatory node in metabolism. We aim to interrogate this concept by perturbing this DNL pathway through selective KO of DNL enzymes ATP citrate lyase (ACLY) and fatty acid synthase (FASN). Our preliminary data encourage this approach by revealing that FASN KO upregulates adipocyte neurotrophic factor Neuregulin 4 (Nrg4) and enhances expansion of sWAT sympathetic neurons (SNS), even at thermo-neutrality (30C). Thus, DNL metabolites (Acetyl CoA, Malonyl CoA) or DNL product (Palmitoyl CoA) appear to be intimately linked to controlling adipose SNS activity, adipose energy expenditure and whole body glucose homeostasis. Based on these data, this project seeks to determine the cellular and molecular mechanisms whereby adipocytes can signal to localized SNS neurons and promote the development of Beige adipocytes in sWAT. Aim 1 will determine whether Beige adipocytes in iAdFASNKO mice are derived by direct “conversion” of mature white to beige adipocytes OR by paracrine signaling to induce differentiation of progenitor cells to Beige adipocytes. To address underlying mechanisms, Aim 2 will determine whether Nrg4 (and Negr1, which may also be upregulated) mediates the effect of FASN-depleted adipocytes to cause expansion of the SNS in vivo. This Aim is based on exciting preliminary data showing that conditioned media from such adipocytes cause marked neurite outgrowth in PC-12 neurons in vitro, which is inhibited by Nrg4 silencing. New technology we developed will be used to delete adipocyte Nrg4 and Negr1 using CRISPR-based nanoparticles prior to implantation into recipient mice and analysis of their effects on SNS innervation. Finally, Aim 3 tests whether adipocyte DNL intermediate metabolites Acetyl CoA/Malonyl CoA in iAdFASNKO mice initiate signaling to cause Nrg4 expression and SNS expansion. These adipocyte metabolites in iAdFASNKO mice, and their acetylation and malonylation of cellular proteins, will be reversed by KO of ATP citrate Lyase (ACLY), which generates the Acetyl CoA, in double KO mice. Identifying the DNL intermediates that modulate adipocyte function will enable defining their underlying mechanisms. Together, these experiments have high potential to define novel signaling pathways driven by DNL metabolites that regulate adipose browning and new therapeutic strategies for type 2 diabetes.
摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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MICHAEL P CZECH其他文献

MICHAEL P CZECH的其他文献

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{{ truncateString('MICHAEL P CZECH', 18)}}的其他基金

CRISPR-enhanced adipocyte browning to improve glucose tolerance in obesity and diabetes
CRISPR 增强脂肪细胞褐变以改善肥胖和糖尿病的葡萄糖耐量
  • 批准号:
    10335608
  • 财政年份:
    2021
  • 资助金额:
    $ 58.29万
  • 项目类别:
CRISPR-enhanced adipocyte browning to improve glucose tolerance in obesity and diabetes
CRISPR 增强脂肪细胞褐变以改善肥胖和糖尿病的葡萄糖耐量
  • 批准号:
    10649531
  • 财政年份:
    2021
  • 资助金额:
    $ 58.29万
  • 项目类别:
CRISPR-enhanced adipocyte browning to improve glucose tolerance in obesity and diabetes
CRISPR 增强脂肪细胞褐变以改善肥胖和糖尿病的葡萄糖耐量
  • 批准号:
    10490350
  • 财政年份:
    2021
  • 资助金额:
    $ 58.29万
  • 项目类别:
Adipocyte to neuron signaling in thermogenic programming of white adipose tissue
白色脂肪组织产热编程中的脂肪细胞至神经元信号传导
  • 批准号:
    9889952
  • 财政年份:
    2019
  • 资助金额:
    $ 58.29万
  • 项目类别:
Adipocyte to neuron signaling in thermogenic programming of white adipose tissue
白色脂肪组织产热编程中的脂肪细胞至神经元信号传导
  • 批准号:
    10341100
  • 财政年份:
    2019
  • 资助金额:
    $ 58.29万
  • 项目类别:
Adipocyte to neuron signaling in thermogenic programming of white adipose tissue
白色脂肪组织产热编程中的脂肪细胞至神经元信号传导
  • 批准号:
    10087919
  • 财政年份:
    2019
  • 资助金额:
    $ 58.29万
  • 项目类别:
Insulin Signaling and Metabolic Regulation in Adipocytes
脂肪细胞中的胰岛素信号传导和代谢调节
  • 批准号:
    10194465
  • 财政年份:
    2017
  • 资助金额:
    $ 58.29万
  • 项目类别:
Paracrine Signaling by Kupffer Cells in Hepatic Insulin Resistance
肝胰岛素抵抗中库普弗细胞的旁分泌信号传导
  • 批准号:
    8888443
  • 财政年份:
    2015
  • 资助金额:
    $ 58.29万
  • 项目类别:
Paracrine Signaling by Kupffer Cells in Hepatic Insulin Resistance
肝胰岛素抵抗中库普弗细胞的旁分泌信号传导
  • 批准号:
    9029321
  • 财政年份:
    2015
  • 资助金额:
    $ 58.29万
  • 项目类别:
Mechanisms of insulin resistance related to nonalcoholic steatohepatitis
非酒精性脂肪性肝炎相关胰岛素抵抗机制
  • 批准号:
    10161771
  • 财政年份:
    2015
  • 资助金额:
    $ 58.29万
  • 项目类别:

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乙酰辅酶 A 如何将代谢与基因表达联系起来的分子基础
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