Cellular and molecular mechanisms by which fatty acids regulate adipocyte metabolism

本研究的目的是探讨硬脂酰辅酶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。脂肪细胞是通过以下方式促进全身代谢调节的细胞：1）分泌影响广泛生物功能的因子，包括能量稳态、代谢和胰岛素敏感性，以及2）以甘油三酯的形式储存过量能量。最近引起相当大兴趣的一类化合物是MUFA，其是磷脂、甘油三酯和胆固醇酯形成的关键底物。除了是饮食中消耗的主要脂肪酸之一，MUFA也由SCD从头合成。虽然饮食和从头合成的MUFA之间不存在结构差异，但出现了一个有趣的悖论。膳食MUFA的消耗增加与体重减轻和血压改善、血脂谱和血糖控制相关;然而，相反，增加从头MUFA产生的高SCD活性与脂质蓄积、胰岛素抵抗和肥胖相关。这项研究计划旨在解决这一矛盾，使用细胞生物学，代谢产物分析，基因沉默和生物信息学技术的组合。在分化人脂肪细胞，即从未成熟脂肪细胞向脂质充盈的脂肪细胞的转化中，将用质谱法测量代谢产物。抑制SCD基因表达将减少从头MUFA合成;从而突出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是否被脂肪细胞不同地加工。总之，在这项研究计划中产生的结果将提供关于SCD对脂肪细胞代谢作用的新见解，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。

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.