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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739692
• 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）是重要的分子，可以调节白色脂肪组织（WAT）中众多信号通路，包括脂肪生成，脂质代谢，炎症和脂肪因子的产生。人体中发现的三个最丰富的N3PUFA是α-烯醇酸（ALA），eicosapentaenoic酸（EPA）和Docosahecahexaenoic Acid（DHA）。关于不同N3PUFA的个体作用，鲜为人知，因为ALA通过Delta-6去饱和酶（D6D）酶不断地转化为体内EPA/DHA。为了解决这一现有的知识差距，我由NSERC资助的研究计划使用D6D敲除（D6D-KO）小鼠，这些小鼠无法将ALA转换为EPA/DHA，以促进我们对不同N3PUFA如何调节WAT WAT代谢的基本了解。我们最近发现，与喂食相同饮食的野生型小鼠相比，喂食含有ALA的饮食（但没有EPA/DHA）的D6D-KO小鼠具有较小的WAT脂肪垫和较小的脂肪细胞，或者喂食含有EPA/DHA的D6D-KO小鼠。这一新颖的发现表明，D6D介导的ALA对EPA/DHA的转化对WAT生理学比以前所欣赏的更为重要。因此，我提出的NSERC研究计划的目的是发现ALA影响WAT脂肪垫和脂肪细胞大小的机制，而与EPA/DHA无关。首先，我们将确定在仅喂养ALA的D6D-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D6D-KO小鼠中看到的较小的脂肪细胞是仅喂食ALA的脂肪酸摄取受损和三酰基甘油储存途径，还是脂肪分解和氧化途径的增加。最后，我们将确定与饲喂EPA/DHA的小鼠相比，D6D-KO小鼠是否仅喂食ALA显示较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方面进行所有研究，以进一步促进我们对WAT中不同N3PUFA独立影响的理解。用单个N3PUFA和D6D抑制剂处理的培养的小鼠脂肪细胞细胞中的互补实验将用于验证我们小鼠研究中鉴定出的信号通路中的关键调节点。我们假设在D6D-KO小鼠中看到的较小的脂肪垫 /较小的脂肪细胞仅喂养ALA是脂肪生成受损的结果，以及减少的脂肪酸吸收和三酰基甘油储存途径。此外，我们预计喂食D6D-KO小鼠含有EPA/DHA的饮食将阻止WAT中的这些损害。拟议的研究是原始的和创新的，它基于我们最近的工作，并将大大提高我们对不同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。