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Aims: To investigate the influence of the dose in the FITC-Dextran 4kDa (FD-4) permeability test in an obese mouse model, we tested the bodyweight dose regimen and a lean body mass-based dose regimen in high fat diet (HFD) mice and low fat diet (LFD) mice. We hypothesized that the FD-4 permeation result would be dose-dependent., Methods: The two dose regimens were compared in HFD and LFD mice. Furthermore, we conducted a dose-response study to test the effect of a low or high dose of FD-4 in weight-stratified lean mice. Gene analysis of tight junctions was also carried out., Results: The FD-4 intestinal permeability test was dose-dependent as we found a significant increase in plasma levels of FD-4 in obese mice with the bodyweight dose regimen. However, this difference was not detectable with the lean body mass dose regimen, even with variability-adjusted group sizes. However, the qPCR analysis revealed a decrease in tight junction gene expression in obese mice. Furthermore, we found a dose-dependent significant increase in FD-4 measured in plasma samples in lean mice. No significant difference in intestinal weight was observed between lean and obese mice., Conclusion: Evaluation of the intestinal permeability by FD-4 with the typical bodyweight dose regimen in obese mice will be confounded by the significant difference in dose given when compared to a lean control group. If the test dose is based on lean body mass, no significant difference in intestinal permeability is observed, even with large group sizes. Furthermore, we showed a dose-dependent difference in plasma FD-4 levels in lean mice. Therefore, we conclude that the dose should be based on lean body mass for the FD-4 permeability test if mice with considerable obesity differences are to be compared or to use another test with fixed doses., (© 2023. The Author(s).)

Background and Aims: Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that recapitulates central mechanisms related to vascular smooth muscle cell (VSMC) phenotypic switching and endothelial dysfunction known to operate within the atherosclerotic plaque., Methods: In study A, we employed an electrical current to the carotid artery in ApoE-/- mice to induce severe VSMC injury and death, after which the arteries were allowed to heal for 4 weeks. In study B, a constrictive cuff was added for 6 h at the site of the healed segment to induce a disturbance in blood flow., Results: Compared to vehicle, semaglutide treatment reduced the intimal and medial area by ∼66% (p = 0.007) and ∼11% ( p  = 0.0002), respectively. Following cuff placement, expression of the pro-inflammatory marker osteopontin and macrophage marker Mac-2 was reduced ( p  < 0.05) in the semaglutide-treated group compared to vehicle. GLP-1R were not expressed in murine carotid artery and human coronary vessels with and without atherosclerotic plaques, and semaglutide treatment did not affect proliferation of cultured primary human VSMCs., Conclusions: Semaglutide treatment reduced vessel remodelling following electrical injury and blood flow perturbation in an atheroprone mouse model. This effect appears to be driven by anti-inflammatory and -proliferative mechanisms independent of GLP-1 receptor-mediated signalling in the resident vascular cells. This mechanism of action may be important for cardiovascular protection., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors BR, LMV, MKEO, JCB, AU, CP, RKK, HH, LBK and MN are employees at Novo Nordisk. Novo Nordisk markets semaglutide for the treatment of diabetes and obesity. DMJ, GFS, and JL are present or former employees at University of Copenhagen and have collaborated with Novo Nordisk on this project., (© 2022 The Author(s).)

Exocrine glands in the submucosa of the proximal duodenum secrete alkaline fluid containing mucus to protect the intestinal mucosa from acidic stomach contents. These glands, known as Brunner's glands, express high glucagon-like peptide 1 receptor (GLP-1R) levels. Previous studies have suggested that activation of the GLP-1R induces expression of barrier protective genes in Brunner's glands. Still, the lack of a viable in vitro culture of Brunner's glands has hampered additional studies of the functional consequences of GLP-1R activation. In this study, we established a procedure to isolate and culture cells derived from murine Brunner's glands. The isolated glandular cells retained functional GLP-1R expression in culture, making this in vitro system suitable for the study of GLP-1R activation. We found that cells derived from the Brunner's glands of mice pretreated with semaglutide contained significantly more mucus compared with Brunner's glands from vehicle-treated mice. Our data suggest a protective intestinal response upon semaglutide treatment, but further studies are required to leverage the full potential of cultured Brunner's gland cells.