EYES2024 ESE Young Endocrinologists and Scientists (EYES) 2024 Diabetes, Obesity and Metabolism (13 abstracts)
Effects of semaglutide, peptide YY3-36 and empagliflozin on metabolic dysfunctionsassociated fatty steatotic liver disease in diet-induced obese rats with chronic nitric oxide synthase-inhibition
Niklas Geiger 1,2 , Simon Kloock 1 , Jana Gerner 2 , Aisha-Nike Landthaler 2 , Alexander Georg Nickel 2 , Michael Kohlhaas 2 , Christoph Maack 2 , Andreas Geier 3 , Martin Fassnacht 1 & Ulrich Dischinger & 2
1University Hospital Wuerzburg, Department of Internal Medicine, Division of Endocrinology and Diabetes, Wuerzburg, Germany; 2University Hospital Wuerzburg, Comprehensive Heart Failure Center, Wuerzburg, Germany; 3University Hospital Wuerzburg, Division of Hepatology, Germany
Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common comorbidity of obesity. In this study, we sought to determine hepatic metabolic and mitochondrial effects of the Glucagon-like Peptide-1-agonist semaglutide, the sodium-glucose linked transporter 2-inhibitor empagliflozin and Peptide YY3-36 in diet-induced obese rats with additional chronic inhibition of nitric oxide synthase via Nω-nitro-L-arginine methyl ester (L-NAME), to induce accelerated liver injury.
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: semaglutide, empagliflozin, PYY3-36, semaglutide in combination with empagliflozin or PYY3-36 and saline control. After additional 8 weeks, qRT-PCR and WesternBlot was performed to quantify hepatic mRNA and protein expression of metabolic and inflammatory marker genes. Moreover, mitochondrial respiration and redox status was examined using an Oroboros O2K-Respirometer.
Results: In the liver, the de-novo lipogenesis regulating genes mlXIPL and SREBF-1 were downregulated in the semaglutide and PYY3-36 -mono groups and significantly lower in the semaglutide+PYY3-36 group (P < 0.05) compared to saline treated controls. In the semaglutide+empagliflozin treated group, mRNA levels of IL-1b and TNF-alpha-levels were lower compared to saline. Regarding mitochondrial respiration, fatty acid-dependent state 3 respiration, empagliflozin (P < 0.001) as well as semaglutide+empagliflozin (P < 0.05) decreased O2-consumption significantly in comparison to controls. In uncoupled states, empagliflozin and PYY3-36 mono-treatment decreased the O2-rate significantly (P < 0.05) compared to saline control. Moreover, semaglutide in combination with PYY3-36 lowered O2-consumption and significantly reduced peroxide-production (P < 0.01).
Conclusion: n summary, the presented data indicate a strong improvement of the MASLD. O2-consumption of the respiratory chain in mitochondria is decreased in semaglutide, PYY3-36, and empagliflozin treated rats, supposing reduced metabolic stress in these groups. The strongest effect was detected in semaglutide+PYY3-36 treated animals, which points towards PYY3-36 as a promising additive substance in the treatment of MASLD.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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