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
• 负责人: Mutch, David
• 金额: $ 2.33万
• 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: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528271
• 关键词: Cellular; molecular; mechanisms; fatty; acids

The goal of this research proposal is to investigate the fundamental mechanisms by which stearoyl-CoA desaturase (SCD) and monounsaturated fatty acids (MUFA) regulate adipocyte metabolism. The adipocyte is a cell that contributes to the regulation of whole-body metabolism by: 1) secreting factors that influence a wide range of biological functions, including energy homeostasis, metabolism, and insulin sensitivity, and 2) storing excess energy in the form of triglycerides. One class of compounds that has garnered considerable interest recently are MUFA, which are key substrates in the formation of phospholipids, triglycerides, and cholesterol esters. In addition to being amongst the principle fatty acids consumed in the diet, MUFA are also synthesized de novo by SCD. Although no structural differences exist between dietary and de novo synthesized MUFA, an intriguing paradox has emerged. The increased consumption of dietary MUFA is associated with weight loss and improved blood pressure, plasma lipid profiles, and glycemic control; however, conversely, a high SCD activity that increases de novo MUFA production is related to lipid accumulation, insulin resistance, and obesity. This research proposal aims to address this paradox using a combination of cell biology, metabolite profiling, gene silencing, and bioinformatic technologies. Metabolites will be measured with mass spectrometry in differentiating human adipocytes, i.e. the conversion from premature adipocyte to lipid-engorged adipocyte. Inhibiting SCD gene expression will diminish de novo MUFA synthesis; thereby highlighting the role of SCD on adipocyte cell metabolism. Additionally, SCD-depleted cells will be independently treated with various fatty acids in order to determine whether extracellular MUFA are processed differently by adipocytes. Taken together, the results generated during this research proposal will provide novel insight regarding the role of SCD on adipocyte metabolism, as well as take an important first step towards resolving the MUFA paradox. Additionally, this research will have a long-term impact in the scientific community by improving our understanding of the role of adipocytes in whole-body metabolism.

本研究计划的目的是研究硬脂酰辅酶A去饱和酶（SCD）和单不饱和脂肪酸（MUFA）调节脂肪细胞代谢的基本机制。脂肪细胞是一种通过以下方式调节全身代谢的细胞：1）分泌影响广泛生物功能的因子，包括能量稳态、新陈代谢和胰岛素敏感性；2）以甘油三酯。最近引起人们极大兴趣的一类化合物是 MUFA，它是磷脂、甘油三酯和胆固醇酯形成的关键底物。除了作为饮食中消耗的主要脂肪酸之一之外，MUFA 也是由 SCD 从头合成的。尽管饮食中的 MUFA 和从头合成的 MUFA 之间不存在结构差异，但出现了一个有趣的悖论。饮食中单不饱和脂肪酸摄入量的增加与体重减轻、血压、血脂和血糖控制改善有关；然而，相反，增加 MUFA 生成的高 SCD 活性与脂质积累、胰岛素抵抗和肥胖有关。该研究计划旨在结合细胞生物学、代谢物分析、基因沉默和生物信息学技术来解决这一悖论。将通过质谱法测量分化人类脂肪细胞的代谢物，即从过早的脂肪细胞到脂质充沛的脂肪细胞的转化。抑制SCD基因表达会减少MUFA的从头合成；从而强调了SCD对脂肪细胞代谢的作用。此外，SCD 耗尽的细胞将用各种脂肪酸独立处理，以确定细胞外 MUFA 是否被脂肪细胞以不同的方式处理。总而言之，本研究提案中产生的结果将为 SCD 对脂肪细胞代谢的作用提供新的见解，并为解决 MUFA 悖论迈出重要的第一步。此外，这项研究将通过提高我们对脂肪细胞在全身代谢中的作用的理解，对科学界产生长期影响。