CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China.
EMBO Rep. 2021 Sep 6;22(9):e52247. doi: 10.15252/embr.202052247. Epub 2021 Aug 6.
Our knowledge of the coordination of fuel usage in skeletal muscle is incomplete. Whether and how microRNAs are involved in the substrate selection for oxidation is largely unknown. Here we show that mice lacking miR-183 and miR-96 have enhanced muscle oxidative phenotype and altered glucose/lipid homeostasis. Moreover, loss of miR-183 and miR-96 results in a shift in substrate utilization toward fat relative to carbohydrates in mice. Mechanistically, loss of miR-183 and miR-96 suppresses glucose utilization in skeletal muscle by increasing PDHA1 phosphorylation via targeting FoxO1 and PDK4. On the other hand, loss of miR-183 and miR-96 promotes fat usage in skeletal muscle by enhancing intramuscular lipolysis via targeting FoxO1 and ATGL. Thus, our study establishes miR-183 and miR-96 as master coordinators of fuel selection and metabolic homeostasis owing to their capability of modulating both glucose utilization and fat catabolism. Lastly, we show that loss of miR-183 and miR-96 can alleviate obesity and improve glucose metabolism in high-fat diet-induced mice, suggesting that miR-183 and miR-96 may serve as therapeutic targets for metabolic diseases.
我们对骨骼肌燃料使用协调的了解并不完整。miRNAs 是否以及如何参与氧化的底物选择在很大程度上是未知的。在这里，我们表明，缺乏 miR-183 和 miR-96 的小鼠具有增强的肌肉氧化表型和改变的葡萄糖/脂质稳态。此外，miR-183 和 miR-96 的缺失导致小鼠中相对于碳水化合物，底物利用向脂肪转移。在机制上，miR-183 和 miR-96 的缺失通过靶向 FoxO1 和 PDK4 增加 PDHA1 磷酸化来抑制骨骼肌中的葡萄糖利用。另一方面，miR-183 和 miR-96 的缺失通过靶向 FoxO1 和 ATGL 增强肌肉内脂肪分解来促进骨骼肌中脂肪的利用。因此，我们的研究确立了 miR-183 和 miR-96 作为燃料选择和代谢稳态的主要协调因子，因为它们能够调节葡萄糖利用和脂肪分解。最后，我们表明，miR-183 和 miR-96 的缺失可以减轻肥胖并改善高脂肪饮食诱导的小鼠的葡萄糖代谢，表明 miR-183 和 miR-96 可作为代谢疾病的治疗靶点。
