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CEBPβ regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth.

Authors :
Aghanoori MR
Agarwal P
Gauvin E
Nagalingam RS
Bonomo R
Yathindranath V
Smith DR
Hai Y
Lee S
Jolivalt CG
Calcutt NA
Jones MJ
Czubryt MP
Miller DW
Dolinsky VW
Mansuy-Aubert V
Fernyhough P
Source :
Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2022 Mar 17; Vol. 79 (4), pp. 193. Date of Electronic Publication: 2022 Mar 17.
Publication Year :
2022

Abstract

Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBPβ, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBPβ overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBPβ can be a promising therapeutic approach.<br /> (© 2022. The Author(s).)

Details

Language :
English
ISSN :
1420-9071
Volume :
79
Issue :
4
Database :
MEDLINE
Journal :
Cellular and molecular life sciences : CMLS
Publication Type :
Academic Journal
Accession number :
35298717
Full Text :
https://doi.org/10.1007/s00018-022-04201-9