Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, US.
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, US.
Metabolomics. 2019 Jan 28;15(2):18. doi: 10.1007/s11306-019-1478-5.
As an insulin sensitive tissue, the heart decreases glucose usage during fasting. This response is mediated, in part, by decreasing phosphofructokinase-2 (PFK-2) activity and levels of its product fructose-2,6-bisphosphate. However, the importance of fructose-2,6-bisphosphate in the fasting response on other metabolic pathways has not been evaluated.
The goal of this study is to determine how sustaining cardiac fructose-2,6-bisphosphate levels during fasting affects the metabolomic profile.
Control and transgenic mice expressing a constitutively active form of PFK-2 (Glyco) were subjected to either 12-h fasting or regular feeding. Animals (n = 4 per group) were used for whole-heart extraction, followed by gas chromatography-mass spectrometry metabolic profiling and multivariate data analysis.
Principal component analysis displayed differences between Control and Glyco groups under both fasting and fed conditions while a clear response to fasting was observed only for Control animals. However, pathway analysis revealed that these smaller changes in the Glyco group were significantly associated with branched-chain amino acid (BCAA) metabolism (~ 40% increase in all BCAAs). Correlation network analysis demonstrated clear differences in response to fasting between Control and Glyco groups amongst most parameters. Notably, fasting caused an increase in network density in the Control group from 0.12 to 0.14 while the Glyco group responded oppositely (0.17-0.15).
Elevated cardiac PFK-2 activity during fasting selectively increases BCAAs levels and decreases global changes in metabolism.
作为一种胰岛素敏感组织，心脏在禁食期间会减少葡萄糖的利用。这种反应部分是通过降低磷酸果糖激酶-2（PFK-2）的活性和其产物果糖-2,6-二磷酸的水平来介导的。然而，果糖-2,6-二磷酸在其他代谢途径的禁食反应中的重要性尚未得到评估。
本研究的目的是确定在禁食期间维持心脏果糖-2,6-二磷酸水平如何影响代谢组学特征。
表达组成型激活形式 PFK-2（Glyco）的对照和转基因小鼠分别进行 12 小时禁食或常规喂养。每组（n=4）用于全心脏提取，然后进行气相色谱-质谱代谢谱分析和多变量数据分析。
主成分分析显示，在禁食和喂养条件下，对照和 Glyco 组之间存在差异，而仅在对照动物中观察到对禁食的明显反应。然而，途径分析表明，Glyco 组中这些较小的变化与支链氨基酸（BCAA）代谢显著相关（所有 BCAA 增加约 40%）。相关网络分析表明，在大多数参数中，对照和 Glyco 组对禁食的反应存在明显差异。值得注意的是，禁食导致对照组网络密度从 0.12 增加到 0.14，而 Glyco 组则相反（0.17-0.15）。
在禁食期间，心脏 PFK-2 活性升高选择性地增加了 BCAA 水平，并减少了代谢的全局变化。
