Semaglutide restores astrocyte–vascular interactions and blood–brain barrier integrity in a model of diet-induced metabolic syndrome
Abstract Introduction Metabolic syndrome (MetS) is a metabolic disorder related to obesity and insulin resistance and is the primary determinant of the development of low-intensity chronic inflammation. This continuous inflammatory response culminates in neuroimmune-endocrine dysregulation responsib...
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BMC
2025-01-01
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| Series: | Diabetology & Metabolic Syndrome |
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| Online Access: | https://doi.org/10.1186/s13098-024-01528-0 |
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| author | Vanessa Estato Nathalie Obadia Paulo Henrique Chateaubriand Vivian Figueiredo Marcela Curty Mariana Costa Silva Renata Gabriela Lustosa Ferreira Juliane Santa-Ritta Marcela Campos Baroni Alessandra Aragão João Oliveira Góes Neno Clara Avelar Mendes Vasconcellos Joana Costa D’Avila Marcelo Gomes Granja Hugo Caire de Castro Faria-Neto |
| author_facet | Vanessa Estato Nathalie Obadia Paulo Henrique Chateaubriand Vivian Figueiredo Marcela Curty Mariana Costa Silva Renata Gabriela Lustosa Ferreira Juliane Santa-Ritta Marcela Campos Baroni Alessandra Aragão João Oliveira Góes Neno Clara Avelar Mendes Vasconcellos Joana Costa D’Avila Marcelo Gomes Granja Hugo Caire de Castro Faria-Neto |
| author_sort | Vanessa Estato |
| collection | DOAJ |
| description | Abstract Introduction Metabolic syndrome (MetS) is a metabolic disorder related to obesity and insulin resistance and is the primary determinant of the development of low-intensity chronic inflammation. This continuous inflammatory response culminates in neuroimmune-endocrine dysregulation responsible for the metabolic abnormalities and morbidities observed in individuals with MetS. Events such as the accumulation of visceral adipose tissue, increased plasma concentrations of free fatty acids, tissue hypoxia, and sympathetic hyperactivity in individuals with MetS may contribute to the activation of the innate immune response, which compromises cerebral microcirculation and the neurovascular unit, leading to the onset or progression of neurodegenerative diseases. Objective This study aimed to evaluate the effects of chronic treatment with a GLP-1 receptor agonist (semaglutide) on cerebral microcirculation and neurovascular unit (NVU) integrity. Methods C57BL/6 mice were fed a standard normolipidic diet or a high-fat diet (HFD) for 24 weeks and then treated for 4 weeks with semaglutide (HFD SEMA) or saline solution (HFD SAL). At the end of pharmacological treatment, biochemical analyses, immunohistochemistry analysis, and intravital microscopy of the brain microcirculation were carried out to quantify leukocyte–endothelium interactions and to assess structural capillary density, astrocyte coverage on cerebral vessels and microglial activation. Results We observed that SEMA attenuates high-fat diet-induced metabolic alterations in mice fed with HFD for 24 weeks. SEMA also reversed cerebral microcirculation effects of HFD by reducing capillary rarefaction and the interaction of leukocytes in postcapillary brain venules. The HFD-SEMA group exhibited improved astrocyte coverage on vessels. However, SEMA did not reverse microglial activation. Conclusions Semaglutide can reverse microvascular rarefaction in metabolic syndrome by restoring the integrity of the neurovascular unit. Adverse dietary stimuli can compromise microglial homeostasis that is not reversed by semaglutide. |
| format | Article |
| id | doaj-art-213fda4fe10d4c92b1d36180ae5a13ff |
| institution | OA Journals |
| issn | 1758-5996 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Diabetology & Metabolic Syndrome |
| spelling | doaj-art-213fda4fe10d4c92b1d36180ae5a13ff2025-08-20T01:47:32ZengBMCDiabetology & Metabolic Syndrome1758-59962025-01-0117111610.1186/s13098-024-01528-0Semaglutide restores astrocyte–vascular interactions and blood–brain barrier integrity in a model of diet-induced metabolic syndromeVanessa Estato0Nathalie Obadia1Paulo Henrique Chateaubriand2Vivian Figueiredo3Marcela Curty4Mariana Costa Silva5Renata Gabriela Lustosa Ferreira6Juliane Santa-Ritta7Marcela Campos Baroni8Alessandra Aragão9João Oliveira Góes Neno10Clara Avelar Mendes Vasconcellos11Joana Costa D’Avila12Marcelo Gomes Granja13Hugo Caire de Castro Faria-Neto14Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation–FiocruzLaboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation–FiocruzMedical School, Estácio–IDOMEDMedical School, Estácio–IDOMEDMedical School, Estácio–IDOMEDMedical School, Estácio–IDOMEDMedical School, Estácio–IDOMEDPharmacy School, Universidade Estácio de SáMedical School, Estácio–IDOMEDMedical School, Estácio–IDOMEDMedical School, Estácio–IDOMEDMedical School, Estácio–IDOMEDLaboratory of Pre-clinical Research, Iguaçu UniversityLaboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation–FiocruzLaboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation–FiocruzAbstract Introduction Metabolic syndrome (MetS) is a metabolic disorder related to obesity and insulin resistance and is the primary determinant of the development of low-intensity chronic inflammation. This continuous inflammatory response culminates in neuroimmune-endocrine dysregulation responsible for the metabolic abnormalities and morbidities observed in individuals with MetS. Events such as the accumulation of visceral adipose tissue, increased plasma concentrations of free fatty acids, tissue hypoxia, and sympathetic hyperactivity in individuals with MetS may contribute to the activation of the innate immune response, which compromises cerebral microcirculation and the neurovascular unit, leading to the onset or progression of neurodegenerative diseases. Objective This study aimed to evaluate the effects of chronic treatment with a GLP-1 receptor agonist (semaglutide) on cerebral microcirculation and neurovascular unit (NVU) integrity. Methods C57BL/6 mice were fed a standard normolipidic diet or a high-fat diet (HFD) for 24 weeks and then treated for 4 weeks with semaglutide (HFD SEMA) or saline solution (HFD SAL). At the end of pharmacological treatment, biochemical analyses, immunohistochemistry analysis, and intravital microscopy of the brain microcirculation were carried out to quantify leukocyte–endothelium interactions and to assess structural capillary density, astrocyte coverage on cerebral vessels and microglial activation. Results We observed that SEMA attenuates high-fat diet-induced metabolic alterations in mice fed with HFD for 24 weeks. SEMA also reversed cerebral microcirculation effects of HFD by reducing capillary rarefaction and the interaction of leukocytes in postcapillary brain venules. The HFD-SEMA group exhibited improved astrocyte coverage on vessels. However, SEMA did not reverse microglial activation. Conclusions Semaglutide can reverse microvascular rarefaction in metabolic syndrome by restoring the integrity of the neurovascular unit. Adverse dietary stimuli can compromise microglial homeostasis that is not reversed by semaglutide.https://doi.org/10.1186/s13098-024-01528-0Metabolic syndromeMicrovascular rarefactionNeurovascular unitBBB |
| spellingShingle | Vanessa Estato Nathalie Obadia Paulo Henrique Chateaubriand Vivian Figueiredo Marcela Curty Mariana Costa Silva Renata Gabriela Lustosa Ferreira Juliane Santa-Ritta Marcela Campos Baroni Alessandra Aragão João Oliveira Góes Neno Clara Avelar Mendes Vasconcellos Joana Costa D’Avila Marcelo Gomes Granja Hugo Caire de Castro Faria-Neto Semaglutide restores astrocyte–vascular interactions and blood–brain barrier integrity in a model of diet-induced metabolic syndrome Diabetology & Metabolic Syndrome Metabolic syndrome Microvascular rarefaction Neurovascular unit BBB |
| title | Semaglutide restores astrocyte–vascular interactions and blood–brain barrier integrity in a model of diet-induced metabolic syndrome |
| title_full | Semaglutide restores astrocyte–vascular interactions and blood–brain barrier integrity in a model of diet-induced metabolic syndrome |
| title_fullStr | Semaglutide restores astrocyte–vascular interactions and blood–brain barrier integrity in a model of diet-induced metabolic syndrome |
| title_full_unstemmed | Semaglutide restores astrocyte–vascular interactions and blood–brain barrier integrity in a model of diet-induced metabolic syndrome |
| title_short | Semaglutide restores astrocyte–vascular interactions and blood–brain barrier integrity in a model of diet-induced metabolic syndrome |
| title_sort | semaglutide restores astrocyte vascular interactions and blood brain barrier integrity in a model of diet induced metabolic syndrome |
| topic | Metabolic syndrome Microvascular rarefaction Neurovascular unit BBB |
| url | https://doi.org/10.1186/s13098-024-01528-0 |
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