Objective: To reveal the role and different underlying mechanisms of tirzepatide (Tzp) and semaglutide (Sema) in ameliorating lipid-metabolism disorders.
Methods: High-fat diet, streptozotocin-induced mice and db/db mice were received a daily injection of vehicle or Sema (40.79nmol/kg) or Tzp (16.87nmol/kg) for 5 weeks. Then biochemical indexes and fat content were detected, and histological staining was performed. Lastly, the transcriptome sequencing was performed in all groups of eWAT and liver tissues.
Results: Tzp or Sema reduced fasting blood-glucose, body weight, food intake, triglyceride, cholesterol levels and liver, eWAT, iWAT, BAT weights and alleviated liver pathology in both type 2 diabetic mouse models. Notably, in comparison with Sema, Tzp treatment showed lower body weight, triglyceride levels, iWAT and eWAT weights and adipocyte diameters. But the effects of BAT and liver did not differ between Tzp and Sema. Tzp and Sema regulated many common pathways and specific pathways. Additionally, in the same effect of regulating mitochondrial function, Tzp preferentially regulated endoplasmic reticulum stress, while Sema preferentially regulated inflammation. In the mechanisms of alleviating liver steatosis between Tzp and Sema, NF-kappaB and calcium-mediated signaling were enriched in the Tzp-treated group and the pathways related to cell cycle process and apoptosis were heavily enriched in Sema-treated mice.
Conclusion: The mechanism of attenuating abnormal lipid accumulation of Tzp was attribute to affecting endoplasmic reticulum stress, NF-kappaB and calcium-mediated signaling in eWAT and liver tissues while Sema preferentially regulated inflammation, cell cycle process and apoptosis. Remarkably, a smaller dosage of Tzp delivered more pronounced weight loss compared with high-dose Sema. Our study provided new insights into comparing the effects in reducing lipid-metabolism disorders between Tzp and Sema.
L. Chen: None.
