The role of delta-6 desaturase on omega-3 fatty acid regulation of adipose tissue function
delta-6去饱和酶对omega-3脂肪酸调节脂肪组织功能的作用
基本信息
- 批准号:RGPIN-2020-04278
- 负责人:
- 金额:$ 3.42万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2022
- 资助国家:加拿大
- 起止时间:2022-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Omega-3 polyunsaturated fatty acids (N3PUFA) are important molecules that regulate numerous signaling pathways in white adipose tissue (WAT), including adipogenesis, lipid metabolism, inflammation, and adipokine production. The three most abundant N3PUFA found in the body are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Remarkably little is known about the individual roles of different N3PUFA because ALA is continuously converted into EPA/DHA in the body by the delta-6 desaturase (D6D) enzyme. To address this existing gap in knowledge, my NSERC-funded research program uses D6D knock-out (D6D-KO) mice that are unable to convert ALA into EPA/DHA to advance our fundamental understanding of how different N3PUFA regulate WAT metabolism. We recently discovered that D6D-KO mice fed a diet containing ALA (but no EPA/DHA) have smaller WAT fat pads and smaller adipocytes compared to wild-type mice fed the same diet, or D6D-KO mice fed a diet containing EPA/DHA. This novel discovery revealed that D6D-mediated conversion of ALA to EPA/DHA is of greater importance for WAT physiology than previously appreciated. Therefore, the objective of my proposed NSERC research program is to uncover the mechanisms by which ALA influences WAT fat pad and adipocyte size independent of EPA/DHA. First, we will establish if the expression and activity of key transcription factors that control adipogenesis are impaired in D6D-KO mice fed only ALA. Second, we will determine if the smaller adipocytes seen in D6D-KO mice fed only ALA stems from impaired fatty acid uptake and triacylglycerol storage pathways, or from increased activity of lipolysis and oxidation pathways. Finally, we will determine if D6D-KO mice fed only ALA show higher inflammatory signalling activity compared to mice fed EPA/DHA. We propose to run all studies in functional and dysfunctional adipose tissue, as well as in male and female mice, to further advance our understanding of the independent effects of different N3PUFA in WAT. Complementary experiments in cultured mouse adipocyte cells treated with individual N3PUFA and a D6D inhibitor will be used to validate key regulatory points in signalling pathways that were identified in our mouse studies. We hypothesize that the smaller fat pads / smaller adipocytes seen in D6D-KO mice fed only ALA is a result of both impaired adipogenesis, and reduced fatty acid uptake and triacylglycerol storage pathways. Further, we anticipate that feeding D6D-KO mice a diet containing EPA/DHA will prevent these impairments in WAT. The proposed studies are original and innovative, build upon our recent work, and will significantly advance our understanding of how different N3PUFA regulate WAT function. Further, the proposed research program will provide an outstanding training environment for HQP interested in integrating nutritional biochemistry, physiology, and bioinformatics.
ω-3多不饱和脂肪酸(N3 PUFA)是调节白色脂肪组织(WAT)中的许多信号传导途径的重要分子,包括脂肪形成、脂质代谢、炎症和脂肪因子产生。在人体内发现的三种最丰富的N3 PUFA是α-亚麻酸(ALA),二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)。值得注意的是,人们对不同N3 PUFA的个体作用知之甚少,因为ALA在体内通过δ-6去饱和酶(D 6D)持续转化为EPA/DHA。为了解决这一现有的知识差距,我的NSERC资助的研究计划使用D 6D敲除(D 6D-KO)小鼠,这些小鼠无法将ALA转化为EPA/DHA,以促进我们对不同N3 PUFA如何调节WAT代谢的基本理解。我们最近发现,与喂食相同饮食的野生型小鼠或喂食含EPA/DHA饮食的D 6D-KO小鼠相比,喂食含ALA(但不含EPA/DHA)饮食的D 6D-KO小鼠具有较小的WAT脂肪垫和较小的脂肪细胞。这一新的发现揭示了D 6D介导的ALA向EPA/DHA的转化对于WAT生理学比以前认识到的更重要。因此,我提出的NSERC研究计划的目标是揭示ALA影响WAT脂肪垫和脂肪细胞大小的机制,而不依赖于EPA/DHA。首先,我们将确定在仅饲喂ALA的D 6D-KO小鼠中,控制脂肪形成的关键转录因子的表达和活性是否受损。其次,我们将确定在仅喂食ALA的D 6D-KO小鼠中观察到的较小脂肪细胞是否源于脂肪酸摄取和三酰甘油储存途径受损,或源于脂解和氧化途径活性增加。最后,我们将确定与喂食EPA/DHA的小鼠相比,仅喂食ALA的D 6D-KO小鼠是否表现出更高的炎症信号传导活性。我们建议在功能和功能失调的脂肪组织以及雄性和雌性小鼠中进行所有研究,以进一步推进我们对不同N3 PUFA在WAT中的独立影响的理解。补充实验中培养的小鼠脂肪细胞处理与个别N3 PUFA和D 6D抑制剂将被用来验证关键的调控点,在我们的小鼠研究中确定的信号通路。我们假设,在仅喂食ALA的D 6D-KO小鼠中观察到的较小的脂肪垫/较小的脂肪细胞是脂肪形成受损以及脂肪酸摄取和三酰甘油储存途径减少的结果。此外,我们预计,给D 6D-KO小鼠喂食含有EPA/DHA的饮食将防止WAT中的这些损伤。拟议的研究是原创性和创新性的,建立在我们最近的工作基础上,并将显着推进我们对不同N3 PUFA如何调节WAT功能的理解。此外,拟议的研究计划将提供一个优秀的培训环境,为HQP有兴趣整合营养生物化学,生理学和生物信息学。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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专利数量(0)
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Mutch, David其他文献
Improving Risk Assessment for Metastatic Disease in Endometrioid Endometrial Cancer Patients Using Molecular and Clinical Features: An NRG Oncology/Gynecologic Oncology Group Study.
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2022-08-23 - 期刊:
- 影响因子:5.2
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Maxwell, George Larry
BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma.
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10.1002/cncr.27720 - 发表时间:
2013-01-15 - 期刊:
- 影响因子:6.2
- 作者:
Pennington, Kathryn P.;Walsh, Tom;Lee, Ming;Pennil, Christopher;Novetsky, Akiva P.;Agnew, Kathy J.;Thornton, Anne;Garcia, Rochelle;Mutch, David;King, Mary-Claire;Goodfellow, Paul;Swisher, Elizabeth M. - 通讯作者:
Swisher, Elizabeth M.
Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors
- DOI:
10.1634/theoncologist.2016-0257 - 发表时间:
2017-01-01 - 期刊:
- 影响因子:5.8
- 作者:
Wheler, Jennifer;Mutch, David;Traynor, Anne M. - 通讯作者:
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Effects of cancer treatment on ovarian function
- DOI:
10.1016/j.fertnstert.2008.07.1714 - 发表时间:
2009-08-01 - 期刊:
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Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study.
- DOI:
10.1200/jco.22.01207 - 发表时间:
2022-12-01 - 期刊:
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You, Benoit;Purdy, Christopher;Copeland, Larry J.;Swisher, Elizabeth M.;Bookman, Michael A.;Fleming, Gini;Coleman, Robert;Randall, Leslie M.;Tewari, Krishnansu S.;Monk, Bradley J.;Mannel, Robert S.;Walker, Joan L.;Cappuccini, Fabio;Cohn, David;Muzaffar, Mahvish;Mutch, David;Wahner-Hendrickson, Andrea;Martin, Lainie;Colomban, Olivier;Burger, Robert A. - 通讯作者:
Burger, Robert A.
Mutch, David的其他文献
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{{ truncateString('Mutch, David', 18)}}的其他基金
The role of delta-6 desaturase on omega-3 fatty acid regulation of adipose tissue function
delta-6去饱和酶对omega-3脂肪酸调节脂肪组织功能的作用
- 批准号:
RGPIN-2020-04278 - 财政年份:2021
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
The role of delta-6 desaturase on omega-3 fatty acid regulation of adipose tissue function
delta-6去饱和酶对omega-3脂肪酸调节脂肪组织功能的作用
- 批准号:
RGPIN-2020-04278 - 财政年份:2020
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Cellular and molecular mechanisms by which fatty acids regulate adipose tissue metabolism.
脂肪酸调节脂肪组织代谢的细胞和分子机制。
- 批准号:
RGPIN-2015-05098 - 财政年份:2019
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Cellular and molecular mechanisms by which fatty acids regulate adipose tissue metabolism.
脂肪酸调节脂肪组织代谢的细胞和分子机制。
- 批准号:
RGPIN-2015-05098 - 财政年份:2018
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Modern bomb calorimeter for accurate determination of energy balance in metabolic studies
现代弹式热量计,用于准确测定代谢研究中的能量平衡
- 批准号:
RTI-2019-00572 - 财政年份:2018
- 资助金额:
$ 3.42万 - 项目类别:
Research Tools and Instruments
Cellular and molecular mechanisms by which fatty acids regulate adipose tissue metabolism.
脂肪酸调节脂肪组织代谢的细胞和分子机制。
- 批准号:
RGPIN-2015-05098 - 财政年份:2017
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Cellular and molecular mechanisms by which fatty acids regulate adipose tissue metabolism.
脂肪酸调节脂肪组织代谢的细胞和分子机制。
- 批准号:
RGPIN-2015-05098 - 财政年份:2016
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Cellular and molecular mechanisms by which fatty acids regulate adipose tissue metabolism.
脂肪酸调节脂肪组织代谢的细胞和分子机制。
- 批准号:
RGPIN-2015-05098 - 财政年份:2015
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Cellular and molecular mechanisms by which fatty acids regulate adipocyte metabolism
脂肪酸调节脂肪细胞代谢的细胞和分子机制
- 批准号:
371564-2010 - 财政年份:2014
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
Cellular and molecular mechanisms by which fatty acids regulate adipocyte metabolism
脂肪酸调节脂肪细胞代谢的细胞和分子机制
- 批准号:
371564-2010 - 财政年份:2013
- 资助金额:
$ 3.42万 - 项目类别:
Discovery Grants Program - Individual
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