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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

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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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Authors and Affiliations

  1. Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Jan Detka, Joanna Ślusarczyk, Anna Kurek, Mateusz Kucharczyk, Marta Kubera, Agnieszka Basta-Kaim, Władysław Lasoń & Bogusława Budziszewska

  2. Department of Transplantation, Jagiellonian University Medical College, Kraków, Poland

    Tomasz Adamus & Paweł Konieczny

Authors
  1. Jan Detka
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  2. Joanna Ślusarczyk
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  3. Anna Kurek
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  4. Mateusz Kucharczyk
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  10. Bogusława Budziszewska
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Correspondence to Jan Detka.

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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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