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。脂肪细胞是一种有助于调节全身代谢的细胞：1)分泌影响多种生物功能的因子，包括能量稳态、代谢和胰岛素敏感性；2)以甘油三酯的形式储存多余的能量。一类最近引起相当大兴趣的化合物是MUFA，它是形成磷脂、甘油三酯和胆固醇酯的关键底物。除了在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之间没有结构上的差异，但一个有趣的悖论出现了。饮食中MUFA摄入量的增加与体重减轻、血压、血脂和血糖控制的改善有关；然而，相反，高SCD活性会增加新生MUFA的产生，这与脂质积累、胰岛素抵抗和肥胖有关。本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。代谢产物将用质谱法测量人类脂肪细胞的分化，即从过早脂肪细胞到充脂脂肪细胞的转化。抑制SCD基因表达会减少MUFA的新生合成；从而突出了SCD在脂肪细胞代谢中的作用。此外，scd耗尽的细胞将被不同的脂肪酸独立处理，以确定细胞外MUFA是否被脂肪细胞处理不同。综上所述，在本研究计划中产生的结果将为SCD在脂肪细胞代谢中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。

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.