Endocrine Abstracts

JOINT651

Background: Empagliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, has shown beneficial effects in obesity-related conditions such as heart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the precise cellular mechanisms behind these effects are not fully understood, and there is limited knowledge about gender-specific differences in responsiveness to empagliflozin.

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 and associated comorbidities like HFpEF and MASLD. Following this regimen, the rats received either empagliflozin (EMPA) 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 pyruvate/malate, fatty acids, and succinate as substrates) and redox state with an Oroboros Oxygraph-2k.

Results: In the ECG analysis, the male HFD group exhibited a significantly reduced E/A-ratio with preserved ejection fraction (EF), indicating diastolic dysfunction and an HFpEF phenotype when compared to CO. Cardiac mitochondrial respiration in HFD was significantly lower than in CO but was fully restored by EMPA. EMPA treatment significantly increased the E/A-ratio, in line with a significantly restored mitochondrial redox balance. In female HFD rats, echocardiography similarly showed a significantly reduced E/A-ratio, consistent with diastolic impairment and preserved ejection fraction. Here, EMPA restored the E/A-ratio and mitochondrial respiration was significantly higher compared to HFD. Hepatic histological assessment in the male HFD group indicated increased lipid storage and inflammation with non-significant EMPA-effects. Regarding mitochondrial respiration, the male HFD group exhibited significantly higher respiration rates compared to CO. Mitochondrial O₂ consumption was significantly lower with EMPA compared to HFD in males with stronger effects in females.

Conclusions: Empagliflozin has distinct sex-specific effects in a diet-induced model of HFpEF and MASLD. It enhances cardiac and hepatic mitochondrial function in males while yielding different outcomes in females. Males experience a stronger impact from empagliflozin on cardiac mitochondrial respiration, while stronger effects on hepatic mitochondrial respiration could be detected in females. These findings underscore the importance of incorporating sex-based analyses in HFpEF and MASLD research, as responses to empagliflozin may vary significantly between sexes, potentially influencing treatment strategies.