Effects of Semaglutide on Hepatocyte Metabolism In Vitro

• Grant number: 25/21802-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2025
• End date: October 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Éverton Lopes Vogt
• Grantee: Mariana Akemi Marques Yokoyama
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 20/06970-5 - Mitochondrial ion transporters as sensors and regulators in energy metabolism, AP.TEM

Abstract

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) widely used in the treatment of type 2 diabetes and obesity, with benefits that include improved glycemic homeostasis, reduced adiposity, and cardioprotective effects. Recent evidence also suggests potential beneficial actions in the liver, such as reduced steatosis and improved hepatic inflammation. However, the molecular mechanisms involved remain poorly understood, particularly due to the controversy surrounding the presence and functionality of GLP-1 receptors in hepatocytes. This project aims to systematically investigate the direct effects of semaglutide on the energy and lipid metabolism of AML12 hepatocytes cultured in vitro. Mitochondrial bioenergetics will be assessed through extracellular flux analysis, along with the expression of genes and proteins related to lipogenesis, ¿-oxidation, and gluconeogenesis, as well as lipid accumulation via Oil Red O and BODIPY staining. Mitochondrial morphology will be quantified using fluorescence microscopy. It is hypothesized that semaglutide will enhance oxidative capacity and mitochondrial content, reduce lipid accumulation, and positively modulate pathways such as AMPK/PGC1¿ while inhibiting lipogenic factors like SREBP1c and FAS. The expected findings may clarify potential off target effects and interactions with alternative receptors, expanding the understanding of the extra-pancreatic actions of GLP-1RAs. This study seeks to fill critical gaps in the understanding of semaglutide's role in hepatic physiology and provide insights for the development of targeted therapies for metabolic liver diseases.