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Semaglutide interferes with postnatal growth in a diet-dependent manner

ABSTRACT: 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. 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. 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 could interfere with the growth of malnourished juvenile mice by altering circadian rhythm and thermogenesis. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE266477 | GEO | 2024/05/07

REPOSITORIES: GEO

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Project description:The thymus is one of the most affected organs during malnutrition, exhibiting atrophy and thymocyte depletion, characteristics that are also observed in several infectious diseases. The detrimental effects of malnutrition on immune responses to pathogens have long been recognized and it is considered a main risk factor for various infectious diseases, including visceral leishmaniasis (VL). However, the thymus has been barely studied during malnutrition and Leishmania infantum infection association. Protein malnutrition modifies intrathymic communication in L. infantum infected BALB/c mice by altering the abundance of proteins secreted to the thymic interstitial fluid (IF). We identified and compared protein abundance in the thymic IF samples from BALB/c mice that were fed with control protein (14%, CP) or low protein (4%, LP) isocaloric diets, followed by infection with L. infantum. By means of a quantitative proteomics approach using iTRAQ we identified 280 proteins of which 81% were reported as secreted by exosomes and 42% were previously described as secreted by thymic epithelial cells. LP-infected (LPi) animals showed a significant decrease in exosomal proteins, suggesting that exosomal carrier system is dysregulated in malnourished animals. LPi mice also exhibited an increase in the relative abundance of proteins involved in lipid metabolism and tricarboxylic acid cycle, suggestive of a non-proliferative microenvironment. Accordingly, flow cytometry analysis revealed that protein malnutrition decreases the proliferation of single positive and double positive T cells. Proteins engaged in glycolysis, protein ubiquitination and mRNA processing were significantly decreased. In addition, a significant decrease in the abundance of galectin-1 and increase of plasminogen were observed in malnourished animals. Together, the reduced cortical area, decreased proliferation, increased abundance of lipid- and tricarboxylic acid cycle-related proteins, and altered abundance of galectin-1 and plasminogen indicate a dysfunctional thymic microenvironment, where T cell migration, proliferation and maturation are compromised, contributing for the thymic atrophy observed in malnourished animals. All these alterations affect the control of the local and systemic infection, resulting in an impaired response to L. infantum infection.

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Semaglutide interferes with postnatal growth in a diet-dependent manner

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