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.

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).

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.

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.

Hepatic mTORc1/AMPK pathway of obese mice treated by semaglutide. The high-fat diet intake stimulates the hepatic PI3k gene (Pi3kc2a), increasing Akt and activating mTORc1. These findings enhance the expression of 4ebp1 (Ei4ebp1), improving insulin signaling and proliferation through S6k1 (Rps6k1b) and Eef2. Therefore, AMPK (Prkag2) is impaired, decreasing the action of Ulk3 in autophagy, hindering cell apoptosis, and decreasing Sirt1. Moreover, there are increased gene expressions of Lxr (Nr1h3), Srebp1c (Srebf1), Acc1 (Acaca), Chrebp1 (Mlxipl), with a more significant stimulus in cholesterol production, fatty acid biosynthesis, and lipid metabolism. In addition, these findings generate a decrease in Acc2 (Acacb), impairing beta-oxidation. Semaglutide mitigated the mTOR pathway and improved the AMPK pathway in the liver of obese animals.