Role of dietary derived propionyl-CoA in the prevention of obesity-induced health impairments

最近的数据提供了证据，证明由肠道发酵纤维产生的丙酸（Pr）可以改善饮食诱导的肝脂肪变性和胰岛素抵抗。相应的，血浆磷脂中的奇链脂肪酸（OCFA）被诱导，表明丙酰辅酶a （Pr-CoA）被用于脂肪酸合成。除了作为乳制品摄入量的生物标志物外，OCFA还与改善胰岛素敏感性和2型糖尿病风险有关。然而，因果关系尚未阐明。由于血浆中可检测到的OCFA含量很低，我假设有益的关联是Pr-CoA可用性增加的结果。为了得出因果结论，我将在小鼠中进行饮食干预研究，通过比较Pr、Pr- coa和OCFA的循环浓度，确定哪些饮食成分的代谢Pr- coa浓度会增加。为了系统地检查代谢改善的因果关系，将使用额外的ocfa补充饮食来区分Pr-CoA-和ocfa介导的健康影响。通过细胞培养实验对肝脏机制的后续分析将揭示潜在的机制。该项目对于了解Pr-CoA如何改变代谢特性，进而改善全身能量代谢具有重要意义。

Recent data provide evidence for an improvement of diet-induced hepatic steatosis and insulin resistance by propionate (Pr) which is intestinally produced from fermentable fiber. Correspondingly, odd-chain fatty acids (OCFA) in plasma phospholipids are induced indicating that propionyl-CoA (Pr-CoA) is used for fatty acid synthesis. Beside their consideration as biomarkers for dairy intake, OCFA are related to an improved insulin sensitivity and type 2 diabetes risk. However, causal relationships are not elucidated. Since the detectable amount of OCFA in plasma is low, I hypothesize that beneficial associations are rather a consequence of increased Pr-CoA availability. For drawing causal conclusions I will perform dietary intervention studies in mice to identify by which dietary components metabolic Pr-CoA concentrations are increased by comparing circulating concentrations of Pr, Pr-CoA and OCFA. To systematically examine the causality of metabolic improvements, an additional OCFA-supplemented diet will be used to differentiate between Pr-CoA- and OCFA-mediated health effects. Subsequent analysis of hepatic mechanisms supported by cell culture experiments will be carried out to uncover underlying mechanisms. This project is important to understand how Pr-CoA can change metabolic characteristics and further improve whole body energy metabolism.