ECEESPE2025 Oral Communications Oral Communications 15: Metabolism, Nutrition and Obesity (6 abstracts)
Sex-specific molecular effects of semaglutide on cardiac and hepatic mitochondrial respiration and cellular redox state in HFpEF and MASLD
Niklas Geiger 1,2 , Michael Kohlhaas 2 , Alexander Nickel 1 , Palina Zytner 1,2 , Simon Kloock 1 , Michael Matz 1,2 , Mia Külzer 2 , Jessica Ulrich 3 , Vasco Sequiera 2 , Martin Fassnacht 3 , Andreas Geier 4 , Christioph Maack 1 & Ulrich Dischinger 1,2
1University Hospital Würzburg, Department of Endocrinology and Diabetes, Würzburg, Germany; 2University Hospital Würzburg, Comprehensive Heart Failure Center, Würzburg, Germany; 3University of Würzburg, Pharmacology and Toxicology, Würzburg, Germany; 4University Hospital Würzburg, Department of Hepatology, Würzburg, Germany
JOINT266
Background: Glucagon-like peptide (GLP)-1 receptor agonists, such as semaglutide, are known to have beneficial effects on obesity-related diseases such as heart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated steatotic liver disease (MASLD). However, cellular mechanisms underlying these effects remain poorly understood. Moreover, the gender-specificity of these effects is unclear.
Methods: Male and female wistar rats were fed either standard chow (CO) or a high-fat/fructose (HFD) diet combined with L-NAME for 8 weeks to induce obesity, hypertension and associated comorbidities like HFpEF and MASLD. Following this regimen, the rats received either semaglutide (SEMA) or saline (HFD) for additional 8 weeks, with ad libitum access to either HFD or a low-fat/high-fructose diet. Echocardiography (ECG) was conducted at the end of treatment. Histological assessment for H.E., OilRed and CD3 was performed in hepatic tissue. Isolated cardiomyocytes were evaluated for mitochondrial redox state, while isolated cardiac and hepatic mitochondria were subjected to high-resolution respirometry to assess oxygen consumption (with carbohydrates and fatty acids as substrates) and redox state with an Oroboros Oxygraph-2k.
Results: In ECG, the male HFD group exhibited a significantly reduced E/A-ratio with preserved ejection fraction, indicating diastolic dysfunction and an HFpEF phenotype when compared to the healthy CO group. SEMA normalized the E/A-ratio, in line with a significantly improved mitochondrial redox balance compared to HFD. Cardiac mitochondrial respiration, was significantly reduced in the HFD group, and was fully restored by SEMA. In female HFD rats, ECG showed a significantly reduced E/A-ratio. However, the mitochondrial redox state remained similar to CO. Here, SEMA did not normalize the E/A-ratio and mitochondrial respiration was unaffected. Characteristic for MASLD, hepatic histological assessment in the male HFD group indicated increased lipid storage and inflammation. Hepatic mitochondrial respiration in males was significantly higher in the HFD group compared to CO. While SEMA improved histological parameters, only a partial reduction of mitochondrial respiration could be detected. In females, mitochondrial respiration was also significantly increased compared to CO. Here, SEMA treatment significantly reduced cellular respiration and redox state.
Conclusion: Semaglutide exhibits sex-specific effects in a diet-induced model of HFpEF and MASLD, improving cardiac mitochondrial function in males while providing less pronounced effects in females. Regarding hepatic mitochondrial respiration, semaglutide treatment led to stronger effects in females. These results highlight the critical need to incorporate sex-based analyses in research on HFpEF and MASLD, given the variations in responses to semaglutide between genders, potentially having implications for treatment strategies.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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