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. 2025 Apr;45(4):e70068.
doi: 10.1111/liv.70068.

Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice

Rafael Calais Gaspar  1 , Ana Paula Azevêdo Macêdo  1 , Susana Castelo Branco Ramos Nakandakari  2 , Vitor Rosetto Muñoz  1 , Gabriela Ferreira Abud  3 , Renan Fudoli Lins Vieira  1 , Ivo Vieira de Sousa Neto  3 , Isadora Carolina Betim Pavan  4 , Luiz Guilherme Salvino da Silva  4 , Fernando Moreira Simabuco  4   5 , Adelino S R da Silva  3 , Wilson Salgado Junior  6 , Julio Sergio Marchini  7 , Carla Barbosa Nonino  8 , Dennys Esper Cintra  2   9 , Eduardo Rochete Ropelle  1   9 , Utpal B Pajvani  10 , Ellen Cristini de Freitas  3 , José Rodrigo Pauli  1   9
Affiliations

Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice

Rafael Calais Gaspar et al. Liver Int. 2025 Apr.

Abstract

Background and aims: Notch1 protein plays a significant role in hepatic metabolism, as evidenced by its correlation with insulin resistance in the livers of obese individuals, making it an intriguing research target. Therefore, this study aims to investigate the impact of aerobic exercise on Notch1 pathways in the hepatic tissue of obese mice and its role in controlling hepatic metabolism.

Methods: Therefore, we conducted a cross-sectional study utilising liver biopsies from lean and obese humans, as well as an intervention study involving mice subjected to a high-fat diet. The obese-trained mice group underwent a treadmill-running protocol for 4 weeks.

Results: Our findings revealed that obese individuals exhibited increased NOTCH1 mRNA levels compared to lean subjects. The detrimental effects of Notch1 signalling were confirmed by Notch1-overexpressed HepG2 cell lines. Obese mice with higher hepatic Notch1 signalling demonstrated a reduction in this pathway when subjected to a 4-week treadmill running. Another benefit noticed in this trained group was the amelioration of insulin resistance, as well as a reduction in pyruvate intolerance and gluconeogenic enzymes. Additionally, we observed that these protective findings were accompanied by a decrease in mTORC1 pathway activity and lipid accumulation in the liver. Pharmacological inhibition of Notch1 in obese mice led to an increase in mitochondrial respiration in the liver.

Conclusions: We conclude that Notch1 signalling may be a potentially useful therapeutic target in obesity, while aerobic exercise training suppresses the Notch1 pathway in the liver, contributing to the regulation of hepatic glucose and lipid metabolism in obese mice.

Keywords: MAFLD; gluconeogenesis; lipogenesis; physical exercise.

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References

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