The mTORC1/AMPK pathway plays a role in the beneficial effects of semaglutide (GLP-1 receptor agonist) on the liver of obese mice.

Abstract

PURPOSE:

The liver regulates lipid metabolism. Decreasing mTOR (mechanistic target of rapamycin complex 1) and enhancing AMPK (AMP-activated protein kinase) help degrade hepatic diet-induced accumulated lipids. Therefore, the glucagon-like peptide type 1 receptor agonist (GLP-1) is indicated to treat obesity-related liver metabolic alterations. Then, we investigated the effects of semaglutide (recent GLP-1) by analyzing the liver mTORC1/AMPK pathway genes in obese mice.

BASIC PROCEDURES:

C57BL/6 male mice were separated into two groups and submitted for 16 weeks of obesity induction. Then they were treated for an additional four weeks with semaglutide (subcutaneous, 40 μg/kg once every three days). The groups formed were: C, control group; CS, control group plus semaglutide; HF, high-fat group; HFS, high-fat group plus semaglutide. Next, the livers were dissected, and rapidly fragments of all lobes were kept and frozen at -80° C for analysis (RT-qPCR).

MAIN FINDINGS:

Liver markers for the mTOR pathway associated with anabolism and lipogenesis de novo were increased in the HF group compared to the C group but comparatively attenuated by semaglutide. Also, liver markers for the AMPK pathway, which regulates chemical pathways involving the cell's primary energy source, were impaired in the HF group than in the C group but partly restored by semaglutide.

CONCLUSION:

the mTOR pathway was attenuated, and the insulin signaling and the AMPK pathway were enhanced by semaglutide, ameliorating the liver gene expressions related to the metabolism of obese mice. These findings are promising in delaying the progression of nonalcoholic fatty liver disease.

• Authors: Pedro Henrique Reis-Barbosa, Ilitch Aquino Marcondes-de-Castro, Thatiany de Souza Marinho, Marcia Barbosa Aguila, Carlos Alberto Mandarim-de-Lacerda
• Journal: Clinics and research in hepatology and gastroenterology (Clin Res Hepatol Gastroenterol) 2022 Jun-Jul Vol. 46 Issue 6 Pg. 101922 ISSN: 2210-741X [Electronic] France
• PMID: 35427802 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Chemical References

• Glucagon-Like Peptide-1 Receptor
• semaglutide
• Glucagon-Like Peptides
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Animals
• Glucagon-Like Peptide-1 Receptor (agonists)
• Glucagon-Like Peptides (pharmacology)
• Liver (drug effects, metabolism)
• Male
• Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (drug therapy, genetics, metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases