Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China.
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China.
Nat Commun. 2024 Jun 4;15(1):4757. doi: 10.1038/s41467-024-48970-2.
Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.
司美格鲁肽是一种胰高血糖素样肽-1 受体激动剂，由于其对能量代谢的影响，临床上被用作降血糖和减肥药物。在心力衰竭中，由于线粒体功能改变和糖酵解增加，能量产生受损。然而，司美格鲁肽在压力超负荷下对心肌细胞代谢的影响尚不清楚。在这里，我们证明司美格鲁肽可改善压力超负荷诱导的心力衰竭小鼠模型的心脏功能，并减少心肌肥厚和纤维化。司美格鲁肽在慢性应激下可维持线粒体结构和功能。代谢组学显示，司美格鲁肽通过促进丙酮酸进入三羧酸循环和增加脂肪酸氧化来减少线粒体损伤、脂质积累和 ATP 缺乏。转录分析表明，司美格鲁肽通过 PI3K/AKT 通路中的 Creb5/NR4a1 轴调节心肌能量代谢，降低 NR4a1 的表达及其向线粒体的易位。NR4a1 敲低可改善心脏的线粒体功能障碍和异常葡萄糖及脂质代谢。这些发现表明，司美格鲁肽可能通过调节能量代谢成为改善心脏重构的治疗药物。
