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GLP 1 secretion by microglial cells and decreased cns expression in obesity
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0002-6668-1094
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0002-0308-1964
Vise andre og tillknytning
2012 (engelsk)Inngår i: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 9, s. 276-Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: Type 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies. T2D patients have a deficiency in the intestinal incretin hormone GLP-1, which has been shown to exert neuroprotective and anti-inflammatory properties in the brain. Methods: Here we investigate potential sources of GLP-1 in the CNS and the effect of diabetic conditions on the proglucagon mRNA expression in the CNS. The obese mouse model ob/ob, characterized by its high levels of free fatty acids, and the microglia cell line BV-2 were used as models. mRNA expression and protein secretion were analyzed by qPCR, immunofluorescence and ELISA. Results: We show evidence for microglia as a central source of GLP-1 secretion. Furthermore, we observed that expression and secretion are stimulated by cAMP and dependent on microglial activation state. We also show that insulin-resistant conditions reduce the central mRNA expression of proglucagon. Conclusion: The findings that microglial mRNA expression of proglucagon and GLP-1 protein expression are affected by high levels of free fatty acids and that both mRNA expression levels of proglucagon and secretion levels of GLP-1 are affected by inflammatory stimuli could be of pathogenic importance for the premature neurodegeneration and cognitive decline commonly seen in T2D patients, and they may also be harnessed to advantage in therapeutic efforts to prevent or treat such disorders.

sted, utgiver, år, opplag, sider
2012. Vol. 9, s. 276-
Emneord [en]
Glucagon-like peptide-1, Microglia, Neuroinflammation, Neuroprotection, Proglucagon
HSV kategori
Identifikatorer
URN: urn:nbn:se:su:diva-88298DOI: 10.1186/1742-2094-9-276ISI: 000314754300001OAI: oai:DiVA.org:su-88298DiVA, id: diva2:612173
Merknad

AuthorCount:5;

Tilgjengelig fra: 2013-03-20 Laget: 2013-03-12 Sist oppdatert: 2018-01-11bibliografisk kontrollert
Inngår i avhandling
1. Neuroinflammation in Alzheimer’s disease and obesity
Åpne denne publikasjonen i ny fane eller vindu >>Neuroinflammation in Alzheimer’s disease and obesity
2013 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Alzheimer’s disease (AD) and obesity are both major problems in the western world. Although they may appear to have little in common at first glance, they are both characterized by chronic inflammation. Exactly how inflammation affects these disorders is far from clear. Microglia, the resident immune cells of the brain, can take on different phenotypes in response to inflammatory stimuli. They can become classically or alternatively activated, where they secrete pro- or anti-inflammatory cytokines respectively. The inflammatory response is to a large part regulated by transcription factors, such as C/EBPδ, which regulate gene expression. The aim of this thesis was to investigate 1) effects of the Alzheimer’s related peptide amyloid-β (Aβ) on C/EBPδ in astrocytes and microglia during inflammatory conditions, 2) how microglia is affected by elevated levels of free fatty acids (FFAs) occurring in obesity and 3) possible cellular sources of the neuroprotective peptide GLP-1 in the brain. In paper I we found that IL-1β-induced C/EBPδ appears to be blocked by Aβ fibrils but not Aβ oligomers in mixed glial cells. In paper II we found that the decreased levels of C/EBPδ were limited to astrocytes under inflammatory conditions and that there was no blocking of IL-1β-induced C/EBPδ in microglia. In paper III we found that the FFA palmitate induces an alternative activation in microglia with no effect on the expression of C/EBPδ or the pro-inflammatory cytokines TNF-α, IL-1β and IL-6. However, pre-exposure to palmitate potentiated microglia phagocytosis and changed the mRNA expression profile of some pro-inflammatory cytokines in response to inflammatory stimuli. In paper IV we found microglia to be a novel source of secreted GLP-1. Further, we found that the GLP-1 secretion could be decreased by inflammatory stimuli. In summary, the inflammatory response of C/EBPδ in AD appears to be disturbed. In addition, palmitate affects the response to inflammatory stimuli in microglia.

sted, utgiver, år, opplag, sider
Stockholm: Department of Neurochemistry, Stockholm University, 2013. s. 56
Emneord
Alzheimer's disease, obesity, neuroinflammation
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-95104 (URN)978-91-7447-731-3 (ISBN)
Disputas
2013-11-22, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (engelsk)
Opponent
Veileder
Merknad

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.

Tilgjengelig fra: 2013-10-31 Laget: 2013-10-21 Sist oppdatert: 2018-01-23bibliografisk kontrollert

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