Estato Vanessa, Obadia Nathalie, Chateaubriand Paulo Henrique, Figueiredo Vivian, Curty Marcela, Costa Silva Mariana, Ferreira Renata Gabriela Lustosa, Santa-Ritta Juliane, Campos Baroni Marcela, Aragão Alessandra, Neno João Oliveira Góes, Vasconcellos Clara Avelar Mendes, Costa D'Avila Joana, Gomes Granja Marcelo, Caire de Castro Faria-Neto Hugo
Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation-Fiocruz, Campus Maré. Centro de Pesquisa, Inovação e Vigilância em Covid-19 e Emergências Sanitárias. Endereço: Av. Brasil, 4036-Bloco 2. Manguinhos, Rio de Janeiro, RJ, CEP 21040-361, Brazil.
Medical School, Estácio-IDOMED, Rio de Janeiro, Brazil.
Diabetol Metab Syndr. 2025 Jan 4;17(1):2. doi: 10.1186/s13098-024-01528-0.
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.
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.
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.
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.
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.
代谢综合征（MetS）是一种与肥胖和胰岛素抵抗相关的代谢紊乱，是低强度慢性炎症发展的主要决定因素。这种持续的炎症反应最终导致神经免疫 - 内分泌失调，这是MetS患者代谢异常和发病的原因。MetS患者体内的一些事件，如内脏脂肪组织的积累、血浆游离脂肪酸浓度升高、组织缺氧和交感神经活动亢进，可能有助于激活先天免疫反应，这会损害脑微循环和神经血管单元，导致神经退行性疾病的发生或进展。
本研究旨在评估胰高血糖素样肽 -1（GLP-1）受体激动剂（司美格鲁肽）长期治疗对脑微循环和神经血管单元（NVU）完整性的影响。
将C57BL/6小鼠喂以标准正常脂质饮食或高脂饮食（HFD）24周，然后用司美格鲁肽（HFD SEMA）或生理盐水溶液（HFD SAL）治疗4周。在药物治疗结束时，进行生化分析、免疫组织化学分析和脑微循环活体显微镜检查，以量化白细胞与内皮细胞的相互作用，并评估结构毛细血管密度、脑血管上的星形胶质细胞覆盖情况和小胶质细胞活化。
我们观察到，SEMA减轻了喂食HFD 24周的小鼠中高脂饮食诱导的代谢改变。SEMA还通过减少毛细血管稀疏和脑毛细血管后微静脉中白细胞的相互作用，逆转了HFD对脑微循环的影响。HFD-SEMA组血管上的星形胶质细胞覆盖情况有所改善。然而，SEMA并未逆转小胶质细胞的活化。
司美格鲁肽可通过恢复神经血管单元的完整性来逆转代谢综合征中的微血管稀疏。不良饮食刺激会损害小胶质细胞的稳态，而司美格鲁肽无法逆转这种情况。
