PYY_3-36 potentiates Semaglutide‑mediated mitochondrial modulation in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent comorbidity of obesity. Incretins have emerged as promising therapeutics for MASLD, but their exact mechanisms of action remain unclear. In this study with obese rats, we investigated the cellular effects of the GLP 1 receptor agonist semaglutide and the NPY 2 receptor agonist PYY3 36 on hepatic mitochondria with a focus on mitochondrial oxygen consumption and ROS emission.

Following an eight week feeding period with a high-fat/fructose diet and L NAME, male Wistar rats were randomized into the following treatment groups for further eight weeks: semaglutide (Sema, n=10), PYY3 36 (n=7), semaglutide+PYY3 36 (n=10), food restriction (FR, n=4) and saline control (n=17). Mitochondrial respiration and peroxide emission were examined using an Oroboros O2K Respirometer. HE, Oil Red and Sirius Red stainings were analysed for fibrosis, inflammation and lipid storage.

Hepatic inflammation and histological MASLD score were significantly mitigated by semaglutide and PYY3 36 with additive effects in the combination group. RNA sequencing revealed down regulation of pathways responsible for oxidative phosphorylation and beta oxidation. OxPhos related genes were significantly reduced in Sema+PYY3 36, consistent with mitochondrial respirometry. Hepatic MCAD and PGC 1α expression, key regulators of beta oxidation, was significantly reduced by PYY3 36. Superior effects occurred in the semaglutide+PYY3 36 group with a decline in mitochondrial respiration, decreased mitochondrial H₂O₂ production and reduced hepatocellular stress, while FR and weight loss had no significant impact on mitochondrial respiration or OxPhos regulating genes.

This study highlights the favourable effects of semaglutide and PYY3 36 mitigating mitochondrial dysfunction in MASLD, providing insight into their possible molecular mechanisms.