Endocrine Abstracts

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 YY_3-36 in diet-induced obese rats with additional chronic inhibition of nitric oxide synthase via N^ω-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, PYY_3-36, semaglutide in combination with empagliflozin or PYY_3-36, 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 PYY_3-36 -mono groups and significantly lower in the semaglutide+PYY_3-36 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+PYY_3-36 (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 PYY_3-36 mono-treatment decreased the O₂-rate significantly (P<0.05) compared to saline control. Moreover, semaglutide in combination with PYY_3-36 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, PYY_3-36, and empagliflozin treated rats, supposing reduced metabolic stress in these groups. The strongest effect was detected in semaglutide+PYY_3-36 treated animals, which points towards PYY_3-36 as a promising additive substance in the treatment of MASLD.