Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a frequent comorbidity of obesity. Incretins like glucagon-like peptide (GLP) -1 receptor agonists e.g, semaglutide have already emerged as promising therapeutics for HFpEF, but their exact mechanisms of action are still unknown. In this study with diet-induced obese HFpEF rats with chronic NO-synthase inhibition, we investigated the cellular individual and combined effects of semaglutide and the neuropeptide (NPY)-2 receptor agonist peptide YY3-36 (PYY3-36) on cardiac energy metabolism. Methods Following an eight-week feeding period with a high-fat/fructose-diet (HFD) and L- NAME, male Wistar rats were randomized into the following treatment groups for further 8 weeks: Semaglutide (Sema), PYY3-36, semaglutide in combination with PYY3-36 (Sema+PYY3-36) and saline treated control (HFpEF). Controls received standard chow without L-NAME (Ctrl). After 16 weeks, blood pressure measurement, echocardiography, and cardiac 18F-FDG PET-CT imaging were performed. Isolated cardiomyocytes were analyzed for cytosolic Ca2+ handling, mitochondrial redox state, and mitochondrial membrane potential. Mitochondrial respiration, oxidative stress, and Ca2+ retention capacity were assessed in isolated cardiac mitochondria. RNA sequencing and Proteomics was performed for pathways and gene expression analysis. Results The HFpEF group showed diastolic dysfunction with preserved fractional shortening and increased intracellular Ca2+ and Ca2+ transient amplitude, consistent with an HFpEF phenotype (p0.01). Sema+PYY3-36 significantly rescued the E/A ratio compared to the individual application of Sema and PYY3-36 (p0.05). The combination of Sema+PYY3-36 and PYY3-36 alone significantly rescued diastolic sarcomere length (p0.01). Mitochondrial respiration was significantly reduced (p0.001), while ROS-emission was significantly increased in the HFpEF group compared to Ctrl and rescued in Sema and PYY3-36 individual with no additive effects in Sema+PYY3-36 but in cellular redox state (p0.01). PET-CT showed significantly reduced myocardial 18F-FDG uptake, consistent with rescued redox imbalance due to reduced glycolytic flux (p0.05). Related to this, RNA sequencing showed downregulated oxidative phosphorylation pathways in the HFpEF group compared to Ctrl with the strongest effects in Sema+PYY3-36 (p0.0001). Conclusions This study highlights the additive effects of semaglutide+PYY3-36 mitigating cardiac mitochondrial dysfunction, sarcomere shortening and E/A ratio in DIO HFpEF rats. These results provide novel insights into molecular mechanisms following the upcoming twincretin approach.
Geiger et al. (Mon,) studied this question.