Rahim Mohsin, Bednarski Tomasz K, Hasenour Clinton M, Banerjee Deveena R, Trenary Irina, Young Jamey D
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
Cell Rep. 2025 May 27;44(5):115591. doi: 10.1016/j.celrep.2025.115591. Epub 2025 Apr 16.
We present an isotope-based metabolic flux analysis (MFA) approach to simultaneously quantify metabolic fluxes in the liver, heart, and skeletal muscle of individual mice. The platform was scaled to examine metabolic flux adaptations in age-matched cohorts of mice exhibiting varying levels of chronic obesity. We found that severe obesity increases hepatic gluconeogenesis and citric acid cycle flux, accompanied by elevated glucose oxidation in the heart that compensates for impaired fatty acid oxidation. In contrast, skeletal muscle fluxes exhibit an overall reduction in substrate oxidation. These findings demonstrate the dichotomy in fuel utilization between cardiac and skeletal muscle during worsening metabolic disease and demonstrate the divergent effects of obesity on metabolic fluxes in different organs. This multi-tissue MFA technology can be extended to address important questions about in vivo regulation of metabolism and its dysregulation in disease, which cannot be fully answered through studies of single organs or isolated cells/tissues.
我们提出了一种基于同位素的代谢通量分析（MFA）方法，用于同时定量单个小鼠肝脏、心脏和骨骼肌中的代谢通量。该平台经过扩展，以研究年龄匹配、患有不同程度慢性肥胖的小鼠队列中的代谢通量适应性。我们发现，严重肥胖会增加肝脏糖异生和柠檬酸循环通量，同时心脏中的葡萄糖氧化增加，以补偿脂肪酸氧化受损。相比之下，骨骼肌通量显示底物氧化总体减少。这些发现表明，在代谢疾病恶化过程中，心脏和骨骼肌在燃料利用上存在二分法，也表明肥胖对不同器官代谢通量有不同影响。这种多组织MFA技术可扩展用于解决有关体内代谢调节及其在疾病中失调方面的重要问题，而这些问题无法通过对单个器官或分离的细胞/组织的研究得到充分解答。
