PYY_3-36 potentiates Semaglutide‑mediated mitochondrial modulation in MASLD

Area of Science:

• Hepatology and metabolic research.
• Mitochondrial biology and function.
• Pharmacological interventions for liver disease.

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in obesity.
• Incretin-based therapies are emerging for MASLD treatment.
• The precise mechanisms of incretin action in MASLD require elucidation.

Purpose of the Study:

• To investigate the cellular effects of semaglutide and PYY3 36 on hepatic mitochondria in obese rats.
• To assess the impact on mitochondrial oxygen consumption and reactive oxygen species (ROS) emission.
• To understand the molecular mechanisms underlying therapeutic effects in MASLD.

Main Methods:

• Obese rats fed a high-fat/fructose diet were treated with semaglutide, PYY3 36, or a combination.
• Mitochondrial respiration and peroxide emission were measured using Oroboros O2K Respirometry.
• Histological analyses (HE, Oil Red, Sirius Red) evaluated liver pathology, and RNA sequencing identified gene expression changes.

Main Results:

• Semaglutide and PYY3 36 significantly reduced hepatic inflammation and MASLD scores, with additive effects in combination.
• RNA sequencing indicated downregulation of oxidative phosphorylation and beta-oxidation pathways.
• The combination therapy demonstrated superior effects, decreasing mitochondrial respiration, H₂O₂ production, and hepatocellular stress.

Conclusions:

• Semaglutide and PYY3 36 exhibit favorable effects in mitigating mitochondrial dysfunction in MASLD.
• These agents offer potential therapeutic strategies by targeting key molecular pathways.
• The study provides mechanistic insights into the benefits of incretin-based therapies for MASLD.