Vitamin D actions in neurons require the PI3K pathway for both enhancing insulin signaling and rapid depolarizing effects.
Brain
Glucose homeostasis
Vitamin D receptor
Journal
The Journal of steroid biochemistry and molecular biology
ISSN: 1879-1220
Titre abrégé: J Steroid Biochem Mol Biol
Pays: England
ID NLM: 9015483
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
18
11
2019
revised:
23
03
2020
accepted:
29
04
2020
pubmed:
15
5
2020
medline:
5
11
2020
entrez:
15
5
2020
Statut:
ppublish
Résumé
Despite correlations between low vitamin D levels and diabetes incidence/severity, supplementation with vitamin D has not been widely effective in improving glucose parameters. This may be due to a lack of knowledge regarding how low vitamin D levels physiologically affect glucose homeostasis. We have previously shown that the brain may be a critical area for vitamin d-mediated action on peripheral glucose levels. However, the mechanisms for how vitamin D acts in the brain are unknown. We utilized a multimodal approach to determine the mechanisms by which vitamin D may act in the brain. We first performed an unbiased search (RNA-sequencing) for pathways affected by vitamin D. Vitamin D (125-dihydroxyvitamin D3; 1,25D3) delivered directly into the third ventricle of obese animals differentially regulated multiple pathways, including the insulin signaling pathway. The insulin signaling pathway includes PI3K, which is important in the brain for glucose regulation. Since others have shown that vitamin D acts through the PI3K pathway in non-neuronal cells (muscle and bone), we hypothesized that vitamin D may act in neurons through a PI3K-dependent pathway. In a hypothalamic cell-culture model (GT1-7 cells), we demonstrate that 1,25D3 increased phosphorylation of Akt in the presence of insulin. However, this was blocked with pre-treatment of wortmannin, a PI3K inhibitor. 1,25D3 increased gene transcription of several genes within the PI3K pathway, including Irs2 and p85, without affecting expression of InsR or Akt. Since we had previously shown that 1,25D3 has significant effects on neuronal function, we also tested if the PI3K pathway could mediate rapid actions of vitamin D. We found that 1,25D3 increased the firing frequency of neurons through a PI3K-dependent mechanism. Collectively, these data support that vitamin D enhances insulin signaling and neuronal excitability through PI3K dependent processes which involve both transcriptional and membrane-initiated signaling events.
Identifiants
pubmed: 32408067
pii: S0960-0760(19)30693-4
doi: 10.1016/j.jsbmb.2020.105690
pmc: PMC7397709
mid: NIHMS1597078
pii:
doi:
Substances chimiques
Insulin
0
Vitamins
0
Calcitriol
FXC9231JVH
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
105690Subventions
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES030285
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
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