Semaglutide normalizes increased cardiomyocyte calcium transients in a rat model of high fat diet-induced obesity.

AIMS: Obesity increases the risk of heart failure with preserved (HFpEF), but not reduced ejection fraction (HFrEF). The glucagon-like peptide-1 receptor agonist (GLP-1-RA) semaglutide improves outcome of patients with obesity with or without HFpEF, while GLP-1-RAs were associated with adverse outcome in patients with HFrEF. Here, we investigate the effect of in vivo treatment with semaglutide on excitation-contraction coupling in a rat model of obesity. METHODS AND RESULTS: Rats received high-fat/high-fructose diet for 8 weeks and were then randomized to semaglutide (HFD/Sema) or vehicle (HFD/Veh) for another 8 weeks, during which they could choose between HFD and a low-fat/high-fructose diet (LFD). Control rats received either standard chow (CON), HFD or LFD only, without treatment. After 16 weeks, sarcomere shortening and cytosolic Ca(2+) concentrations ([Ca(2+)](c)) were determined in isolated cardiomyocytes. Compared with CON, HFD/Veh increased the amplitude of [Ca(2+)](c) transients and systolic sarcomere shortening in absence or presence of β-adrenergic stimulation, which was reversed by HFD/Sema. Caffeine-induced sarcoplasmic reticulum (SR) Ca(2+) release and L-type Ca(2+) channel (LTCC) currents were reduced by HFD/Sema versus HFD/Veh, while SR Ca(2+) ATPase activity remained unaffected. Compared with HFD, LFD increased [Ca(2+)](c) transients and sarcomere shortening further despite similar effects on body weight. CONCLUSIONS: While HFD increased cardiomyocyte [Ca(2+)](c) transients and systolic sarcomere shortening, semaglutide normalized these alterations, mediated by reduced SR Ca(2+) load and LTCC currents. Because increased LTCC currents were previously traced to cardiac hypertrophy, these effects may explain why GLP-1-RAs provide benefits for patients with obesity with or without HFpEF, but rather adverse outcome in HFrEF.