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

Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically employed as both a hypoglycemic and bariatric agent due to its regulatory effects on energy metabolism. In heart failure, mitochondrial oxidative phosphorylation substrates are altered, glycolysis is increased, and intracellular energy production is decreased. However, it remains unclear how cardiomyocytes' metabolic environment under pressure burden responds to Sema-regulated energy metabolism. Here we show, Sema improves cardiac dysfunction and attenuates myocardial hypertrophy and fibrosis in pressure-overload-induced heart failure male mice model. Sema treatment is found to maintain mitochondrial morphology and function under chronic stress-induced damage. Untargeted metabolomics analysis reveals that Sema ameliorates mitochondrial lesions, reduces lipid accumulation, and addresses ATP insufficiency by promoting the glycolytic product, pyruvate, enters the tricarboxylic acid cycle after being converted to acetyl-CoA and increasing β-oxidation. Transcriptional profiling results reveals that Sema exerts its effects on myocardial energy metabolism by regulating Creb5/NR4a1 in the canonical PI3K/AKT pathway. Specifically, Sema reduces the expression of NR4a1 and its translocation from the nucleus to mitochondria. The disorders of mitochondrial function and myocardial glucolipid metabolism were significantly ameliorated after NR4a1 knockdown. Overall, Sema ameliorates myocardial glucose, lipid, and energy metabolism disorders by regulating Creb5/NR4a1, thereby protecting against pathological myocardial remodeling. This finding provides a therapeutic agent for improving pathological myocardial remodeling based on energy metabolic switching.