Laboratory of Computational Biology, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808; Program in Cardiovascular and Metabolic Disorders and Center for Computational Biology, Duke-National University of Singapore Medical School, Singapore 169857, Singapore.
Talaria Antibodies, Inc., Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808; Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808.
J Biol Chem. 2019 Aug 16;294(33):12313-12327. doi: 10.1074/jbc.RA118.006074. Epub 2019 May 16.
Mitochondrial lipid overload in skeletal muscle contributes to insulin resistance, and strategies limiting this lipid pressure improve glucose homeostasis; however, comprehensive cellular adaptations that occur in response to such an intervention have not been reported. Herein, mice with skeletal muscle-specific deletion of carnitine palmitoyltransferase 1b (Cpt1b), which limits mitochondrial lipid entry, were fed a moderate fat (25%) diet, and samples were subjected to a multimodal analysis merging transcriptomics, proteomics, and nontargeted metabolomics to characterize the coordinated multilevel cellular responses that occur when mitochondrial lipid burden is mitigated. Limiting mitochondrial fat entry predictably improves glucose homeostasis; however, remodeling of glucose metabolism pathways pales compared with adaptations in amino acid and lipid metabolism pathways, shifts in nucleotide metabolites, and biogenesis of mitochondria and peroxisomes. Despite impaired fat utilization, Cpt1b mice have increased acetyl-CoA (14-fold) and NADH (2-fold), indicating metabolic shifts yield sufficient precursors to meet energy demand; however, this does not translate to enhance energy status as Cpt1b mice have low ATP and high AMP levels, signifying energy deficit. Comparative analysis of transcriptomic data with disease-associated gene-sets not only predicted reduced risk of glucose metabolism disorders but was also consistent with lower risk for hepatic steatosis, cardiac hypertrophy, and premature death. Collectively, these results suggest induction of metabolic inefficiency under conditions of energy surfeit likely contributes to improvements in metabolic health when mitochondrial lipid burden is mitigated. Moreover, the breadth of disease states to which mechanisms induced by muscle-specific Cpt1b inhibition may mediate health benefits could be more extensive than previously predicted.
骨骼肌中线粒体脂质过载会导致胰岛素抵抗，而限制这种脂质压力的策略可以改善葡萄糖稳态；然而，对于这种干预所发生的全面细胞适应性尚未有报道。在此，我们构建了骨骼肌特异性敲除肉毒碱棕榈酰基转移酶 1b（Cpt1b）的小鼠模型，该酶限制了线粒体脂质的进入，然后用中等脂肪（25%）饮食喂养这些小鼠，并对其进行了多模态分析，将转录组学、蛋白质组学和非靶向代谢组学结合起来，以描述当线粒体脂质负荷减轻时发生的协调的多层次细胞反应。限制线粒体脂肪进入可预测地改善葡萄糖稳态；然而，与氨基酸和脂质代谢途径的适应性、核苷酸代谢物的变化以及线粒体和过氧化物酶体的生物发生相比，葡萄糖代谢途径的重塑相形见绌。尽管脂肪利用率受损，Cpt1b 小鼠的乙酰辅酶 A（14 倍）和 NADH（2 倍）增加，表明代谢转变产生了足够的前体来满足能量需求；然而，这并没有转化为增强能量状态，因为 Cpt1b 小鼠的 ATP 水平低而 AMP 水平高，表明能量不足。将转录组数据与疾病相关基因集进行比较分析，不仅预测了葡萄糖代谢紊乱风险降低，而且与肝脂肪变性、心脏肥大和过早死亡风险降低一致。总的来说，这些结果表明，在能量过剩的情况下，诱导代谢效率低下可能有助于减轻线粒体脂质负担时代谢健康的改善。此外，肌肉特异性 Cpt1b 抑制所诱导的机制可能介导的健康益处的疾病状态范围可能比以前预测的更广泛。
