A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease

Poupon-Bejuit, Laura; Hughes, Michael P.; Liu, W.; Geard, A.; Faour-Slika, N.; Whaler, S.; Massaro, Giulia; Rahim, Ahad A.

doi:10.1038/s41598-022-17338-1

Cited by 10 publications

(16 citation statements)

References 49 publications

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“…The effects of semaglutide during the juvenile period have been poorly investigated in rodents. Indeed, to our knowledge only one study probed the effects of semaglutide after weaning, in a model of infantile neuroaxonal dystrophy, and did not report any interference of semaglutide with the growth of chow diet-fed mice [49]. This is consistent with our data in CD mice.…”

Section: Chronic Semaglutide Treatment Further Compromises Linear Gro...supporting

confidence: 91%

Semaglutide interferes with postnatal growth in a diet-dependent manner

Joly,

Rebiffé,

Dusabyinema

et al. 2024

Preprint

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Objective: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to impact glucose homeostasis and, more recently, the somatotropic axis. While the effects of GLP-1RAs have been extensively studied in the context of diet-induced obesity, their impact on physiology in other nutritional contexts have been less explored. We investigated the potential beneficial effects of the GLP-1RA semaglutide during juvenile protein malnutrition, a dietary challenge known to cause stunted growth and to disrupt metabolic homeostasis. Methods: We used a murine model to assess the effects of twice-weekly subcutaneous injections of semaglutide during juvenile protein malnutrition. Glucose metabolism was evaluated through in vivo oral glucose tolerance test, ex vivo glucose-stimulated insulin secretion in isolated pancreatic islets and histology of the pancreas. We combined linear growth monitoring, analysis of the growth hormone/insulin-like growth factor 1 signaling pathway and liver bulk RNA sequencing to characterize the effects of semaglutide on the somatotropic axis during juvenile protein malnutrition. Results: Semaglutide improved glucose tolerance in control and malnourished mice, but differentially impacted pancreatic islet physiology depending on the dietary protein intake. While semaglutide did not alter growth in control conditions, it further inhibited growth of malnourished mice associated with reduction in fat but not lean mass. Surprisingly, semaglutide had no discernible effect on the functionality of the somatotropic axis in malnourished mice. Liver transcriptomics revealed that semaglutide may interfere with the growth of malnourished juvenile mice by altering circadian rhythm and thermogenesis. Conclusions: Our data reveal that semaglutide interacts differentially with the physiology of juvenile mice depending on their dietary protein intake. We found that semaglutide influences glucose metabolism and linear growth in a diet-dependent manner, underscoring the importance of examining the effects of GLP-1RAs across various nutritional contexts and developmental stages.

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Section: Chronic Semaglutide Treatment Further Compromises Linear Gro...supporting

confidence: 91%

Semaglutide interferes with postnatal growth in a diet-dependent manner

Joly,

Rebiffé,

Dusabyinema

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…The main mechanism of action of these GLP-1RA is the stimulation of the GLP-1R that triggers the activation of several metabolic pathways involved in insulin secretion, lipid metabolism, energy expenditure, pro-survival and anti-apoptotic cellular signaling, and oxidative stress prevention, in several tissues like the pancreas, central nervous system, heart, muscle, kidneys, gut, among others ( 15 ). The wide distribution of the GLP-1R has allowed the study of semaglutide and liraglutide pharmacological protocols to improve metabolic diseases in several experimental models ( 26 , 40 , 48–50 ). The assessment of these GLP-1RA could elucidate the role of these drugs in the cellular signaling process of obese-related diseases, which could support the development of new pharmacological approaches.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, these GLP-1RA medications have also been related to a reduction of neuroinflammation, probably due to its possible role in neuronal insulin signaling pathway restoration ( 49 , 67 , 68 ). Hence, semaglutide and liraglutide could also have the potential to ameliorate neurodegeneration processes observed in pathologies like Alzheimer’s and Parkinson’s diseases, although further research is needed ( 48 , 69 ). Moreover, clinical trials have reported a reduction of the inflammatory C-reactive protein ( 70 ), which could indicate that this drug may also regulate the immune system, although this approach requires further assessment.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity

Tamayo-Trujillo,

Ruiz-Pozo,

Cadena-Ullauri

et al. 2024

Front. Nutr.

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Obesity, a chronic global health problem, is associated with an increase in various comorbidities, such as cardiovascular disease, type 2 diabetes mellitus, hypertension, and certain types of cancer. The increasing global prevalence of obesity requires research into new therapeutic strategies. Glucagon-like peptide-1 receptor agonists, specifically semaglutide and liraglutide, designed for type 2 diabetes mellitus treatment, have been explored as drugs for the treatment of obesity. This minireview describes the molecular mechanisms of semaglutide and liraglutide in different metabolic pathways, and its mechanism of action in processes such as appetite regulation, insulin secretion, glucose homeostasis, energy expenditure, and lipid metabolism. Finally, several clinical trial outcomes are described to show the safety and efficacy of these drugs in obesity management.

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“…Treatment with SEM improved neurodegeneration, especially in the ventral posterior medial and lateral nuclei of the thalamus (VPM/VPL) in Pla2g6−/− mice [ 97 ].…”

Section: Sem Potential Mechanism Of Action In Pdmentioning

confidence: 99%

Unlocking the Potential: Semaglutide’s Impact on Alzheimer’s and Parkinson’s Disease in Animal Models

Meca,

Boboc,

Mititelu-Tartau

et al. 2024

CIMB

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Semaglutide (SEM), a glucagon-like peptide-1 receptor agonist, has garnered increasing interest for its potential therapeutic effects in neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). This review provides a comprehensive description of SEM’s mechanism of action and its effects in preclinical studies of these debilitating conditions. In animal models of AD, SEM has proved beneficial effects on multiple pathological hallmarks of the disease. SEM administration has been associated with reductions in amyloid-beta plaque deposition and mitigation of neuroinflammation. Moreover, SEM treatment has been shown to ameliorate behavioral deficits related to anxiety and social interaction. SEM-treated animals exhibit improvements in spatial learning and memory retention tasks, as evidenced by enhanced performance in maze navigation tests and novel object recognition assays. Similarly, in animal models of PD, SEM has demonstrated promising neuroprotective effects through various mechanisms. These include modulation of neuroinflammation, enhancement of mitochondrial function, and promotion of neurogenesis. Additionally, SEM has been shown to improve motor function and ameliorate dopaminergic neuronal loss, offering the potential for disease-modifying treatment strategies. Overall, the accumulating evidence from preclinical studies suggests that SEM holds promise as a novel therapeutic approach for AD and PD. Further research is warranted to elucidate the underlying mechanisms of SEM’s neuroprotective effects and to translate these findings into clinical applications for the treatment of these devastating neurodegenerative disorders.

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A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease

Cited by 10 publications

References 49 publications

Semaglutide interferes with postnatal growth in a diet-dependent manner

Semaglutide interferes with postnatal growth in a diet-dependent manner

Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity

Unlocking the Potential: Semaglutide’s Impact on Alzheimer’s and Parkinson’s Disease in Animal Models

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