Abstract
Background
In depression, excessive glucocorticoid action may cause maladaptive brain changes, including in the pathways controlling energy metabolism. Insulin and glucagon-like peptide-1 (GLP-1), besides regulation of glucose homeostasis, also possess neurotrophic properties. Current study was aimed at investigating the influence of prenatal stress (PS) on insulin, GLP-1 and their receptor (IR and GLP-1R) levels in the hypothalamus. GLP-1 and GLP-1R were assayed also in the hippocampus and frontal cortex — brain regions mainly affected in depression. The second objective was to determine the influence of exendin-4 and insulin on CRH promoter gene activity in in vitro conditions.
Methods
Adult male PS rats were subjected to acute stress and/or received orally glucose. Levels of hormones and their receptors were assayed with ELISA method. In vitro studies were performed on mHypoA-2/12 hypothalamic cell line, stably transfected with CRH promoter coupled with luciferase.
Results
PS has reduced GLP-1 and GLP-1R levels, attenuated glucose-induced increase in insulin concentration and increased the amount of phosphorylated IR in the hypothalamus of animals subjected to additional stress stimuli, and also decreased the GLP-1R level in the hippocampus. In vitro studies demonstrated that insulin is capable of increasing CRH promoter activity in the condition of stimulation of the cAMP/PKA pathway in the applied cellular model.
Conclusion
Prenatal stress may act as a preconditioning factor, affecting the concentrations of hormones such as insulin and GLP-1 in the hypothalamus in response to adverse stimuli. The decreased GLP-1R level in the hippocampus could be linked with the disturbances in neuronal plasticity.
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Abbreviations
- cAMP:
-
cyclic adenosine monophosphate
- CREB:
-
cAMP response elementbinding protein
- CRH:
-
Corticotropinreleasing hormone
- GLP-1glucagon:
-
like peptide-1
- GLP-1R:
-
glucagonlike peptide-1 receptor
- HPA:
-
hypothalamic — pituitary — adrenal axis
- IR:
-
insulin receptor
- PI3K:
-
phosphatidylinositol3-kinase
- PKA:
-
protein kinase A
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Detka, J., Ślusarczyk, J., Kurek, A. et al. Hypothalamic insulin and glucagon-like peptide-1 levels in an animal model of depression and their effect on corticotropin-releasing hormone promoter gene activity in a hypothalamic cell line. Pharmacol. Rep 71, 338–346 (2019). https://doi.org/10.1016/j.pharep.2018.11.001
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DOI: https://doi.org/10.1016/j.pharep.2018.11.001