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Endocrine Abstracts (2024) 99 RC12.1 | DOI: 10.1530/endoabs.99.RC12.1

ECE2024 Rapid Communications Rapid Communications 12: Diabetes, Obesity, Metabolism and Nutrition | Part II (5 abstracts)

Effects of semaglutide, Peptide YY3-36 and empagliflozin on metabolic dysfunction associated fatty steatotic liver disease in diet-induced obese rats with chronic nitric oxide synthase-inhibition

Niklas Geiger 1 , Simon Kloock 1 , Jana Gerner 2 , Aisha-Nike Landthaler 2 , Alexander Nickel 2 , Michael Kohlhaas 2 , Andreas Geier 3 , Martin Fassnacht 1 & Ulrich Dischinger 1


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, Department of Hepatology, Wuerzburg, Germany


Background and Aims: 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.

Method: 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, a food restricted body weight matched group (BWM) and saline control. After an additional 8 weeks, qRT-PCR was performed to quantify hepatic mRNA expression of metabolic and inflammatory marker genes. Serum was analysed for insulin, glucose, adiponectin and leptin levels. Moreover, in isolated mitochondria, mitochondrial respiration in different states using Oroboros O2K-FluoRespirometer was examined.

Results: In the liver, the de-novo lipogenesis regulating genes MLXIPL and SREBF-1 were downregulated in the BWM, semaglutide and PYY3-36 -mono groups and significantly lower in the semaglutide+PYY3-36 group (P<0.05) compared to saline treated controls. HOMA-index was significantly lower in PYY-mono treated animals (P<0.05) and in the semaglutide+empagliflozin- group (P<0.05), adiponectin-leptin-ratio was significantly higher in semaglutide+PYY3-36 (P<0.01) and BWM treated animals in comparison to saline (P<0.01). Moreover, there was a significant downregulation of IL-1b mRNA in the semaglutide-mono treated group (P<0.05). In the semaglutide+empagliflozin treated group, 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 the uncoupled state, 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 or empagliflozin lowered O2-consumption.

Conclusion: In summary, the presented data indicate a strong improvement of insulin sensitivity shown by presented metabolic parameters and associated genes. 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.

Volume 99

26th European Congress of Endocrinology

Stockholm, Sweden
11 May 2024 - 14 May 2024

European Society of Endocrinology 

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