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
• 负责人: Mutch, David
• 金额: $ 3.42万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716364
• 关键词: role; delta; desaturase; omega; fatty

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.

Omega-3 多不饱和脂肪酸 (N3PUFA) 是调节白色脂肪组织 (WAT) 中众多信号通路的重要分子，包括脂肪生成、脂质代谢、炎症和脂肪因子产生。体内最丰富的三种 N3PUFA 是 α-亚麻酸 (ALA)、二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA)。人们对不同 N3PUFA 的各自作用知之甚少，因为 ALA 在体内通过 delta-6 去饱和酶 (D6D) 不断转化为 EPA/DHA。为了解决这一现有的知识空白，我的 NSERC 资助的研究项目使用无法将 ALA 转化为 EPA/DHA 的 D6D 敲除 (D6D-KO) 小鼠，以加深我们对不同 N3PUFA 如何调节 WAT 代谢的基本理解。 我们最近发现，与饲喂相同饮食的野生型小鼠相比，饲喂含有 ALA（但不含 EPA/DHA）饮食的 D6D-KO 小鼠具有更小的 WAT 脂肪垫和更小的脂肪细胞，或者饲喂含有 EPA/DHA 饮食的 D6D-KO 小鼠。 DHA。这一新发现表明，D6D 介导的 ALA 向 EPA/DHA 的转化对于 WAT 生理学的重要性比之前认识的更为重要。因此，我提出的 NSERC 研究计划的目标是揭示 ALA 独立于 EPA/DHA 影响 WAT 脂肪垫和脂肪细胞大小的机制。首先，我们将确定仅喂食 ALA 的 D6D-KO 小鼠中控制脂肪生成的关键转录因子的表达和活性是否受损。其次，我们将确定仅喂食 ALA 的 D6D-KO 小鼠中所见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，或者源于脂解和氧化途径活性增加。最后，我们将确定仅饲喂 ALA 的 D6D-KO 小鼠是否比饲喂 EPA/DHA 的小鼠表现出更高的炎症信号活性。我们建议在功能性和功能障碍性脂肪组织以及雄性和雌性小鼠中进行所有研究，以进一步加深我们对不同 N3PUFA 在 WAT 中的独立作用的理解。在用单独的 N3PUFA 和 D6D 抑制剂处理的培养的小鼠脂肪细胞中进行的补充实验将用于验证我们在小鼠研究中确定的信号通路中的关键调节点。我们假设，在仅喂食 ALA 的 D6D-KO 小鼠中观察到的较小的脂肪垫/较小的脂肪细胞是脂肪生成受损、脂肪酸摄取和三酰甘油储存途径减少的结果。此外，我们预计用含有 EPA/DHA 的饮食喂养 D6D-KO 小鼠将可以防止 WAT 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，并将显着增进我们对不同 N3PUFA 如何调节 WAT 功能的理解。此外，拟议的研究计划将为有兴趣整合营养生物化学、生理学和生物信息学的 HQP 提供出色的培训环境。