Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis

• Published in: Nature communications 2024-06, Vol.15 (1), p.4757-19, Article 4757
• Main Authors: Ma, Yu-Lan, Kong, Chun-Yan, Guo, Zhen, Wang, Ming-Yu, Wang, Pan, Liu, Fang-Yuan, Yang, Dan, Yang, Zheng, Tang, Qi-Zhu
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 631/443/319; 64/60; 692/4019/592/1540; 692/699/75/230; 82/29; 82/51; 82/58; 82/80; 96/34; 96/44; AKT protein; Animals; Antidiabetics; Cardiomegaly - drug therapy; Cardiomegaly - metabolism; Cardiomyocytes; Congestive heart failure; Cyclic AMP Response Element-Binding Protein - metabolism; Damage accumulation; Disease Models, Animal; Energy metabolism; Energy Metabolism - drug effects; Energy resources; Fibrosis; GLP-1 receptor agonists; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptides - pharmacology; Glucagon-Like Peptides - therapeutic use; Glucose; Glucose metabolism; Glycolysis; Heart failure; Heart Failure - drug therapy; Heart Failure - metabolism; Humanities and Social Sciences; Hypertrophy; Lipid metabolism; Lipid Metabolism - drug effects; Lipids; Male; Metabolism; Metabolomics; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; multidisciplinary; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Overloading; Oxidation; Pharmacology; Pyruvic acid; Science; Science (multidisciplinary); Signal Transduction - drug effects; Structure-function relationships; Substrates; Translocation; Tricarboxylic acid cycle; Ventricular Remodeling - drug effects; Weight loss; Weight reduction
• ISSN: 2041-1723; 2041-1723
• 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. Semaglutide is used for glucose control and weight reduction. Here, the authors show that it enhances myocardial metabolism by targeting Creb5/NR4a1, protecting against cardiac remodeling and offering a therapeutic approach for heart failure through metabolic regulation.