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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.
- 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).)
- Subjects :
- Animals
Antibodies, Neutralizing pharmacology
Axons drug effects
Axons metabolism
Base Sequence
CCAAT-Enhancer-Binding Protein-beta genetics
Cell Respiration drug effects
Cells, Cultured
Diabetes Mellitus, Experimental genetics
Diabetes Mellitus, Type 1 genetics
Diabetes Mellitus, Type 1 pathology
Diabetes Mellitus, Type 2 genetics
Diabetes Mellitus, Type 2 pathology
Ganglia, Spinal drug effects
Ganglia, Spinal metabolism
Gene Expression Regulation drug effects
Glycolysis drug effects
HEK293 Cells
Humans
Insulin-Like Growth Factor I genetics
Liver metabolism
Male
Mitochondria drug effects
Mitochondria metabolism
NFATC Transcription Factors metabolism
Neuronal Outgrowth drug effects
Polymers metabolism
Promoter Regions, Genetic genetics
Protein Transport drug effects
Rats, Sprague-Dawley
Sensory Receptor Cells pathology
Signal Transduction drug effects
Rats
Aging metabolism
Axons pathology
CCAAT-Enhancer-Binding Protein-beta metabolism
Diabetes Mellitus, Experimental metabolism
Diabetes Mellitus, Experimental pathology
Energy Metabolism drug effects
Insulin-Like Growth Factor I metabolism
Sensory Receptor Cells metabolism
Subjects
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