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Chronic stress inhibits hypothalamus–pituitary–thyroid axis and brown adipose tissue responses to acute cold exposure in male rats

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Abstract

Purpose

Cold exposure activates the hypothalamus–pituitary–thyroid (HPT) axis, response blunted by previous acute stress or corticosterone administration. Chronic stressors can decrease serum T3 concentration, and thyrotropin-releasing hormone (Trh) expression in the paraventricular nucleus (PVN), but impact on the response to cold is unknown; this was studied in rats submitted to daily repeated restraint (rRes) that causes habituation of hypothalamus–pituitary–adrenal (HPA) axis response, or to chronic variable stress (CVS) that causes sensitization and hyperreactivity.

Methods

Wistar male adult rats were submitted to rRes 30 min/day, or to CVS twice a day, for 15 days. On day 16, rats were exposed 1 h to either 5 or 21 °C. Parameters of HPT and HPA axes activity and of brown adipose tissue (BAT) cold response were measured; gene expression in PVN and BAT, by RT-PCR; serum hormone concentration by radioimmunoassay or ELISA.

Results

Compared to naïve animals, Crh and corticosterone concentrations were attenuated at the end of rRes, but increased at the end of CVS treatments. Cold exposure increased mRNA levels of Crh, Trh, and serum concentration of thyrotropin in naïve, but not in rRes or CVS rats; corticosterone increased in all groups. Cold induced expression of thermogenic genes in BAT (Dio2 and Ucp1) in naïve but not in stressed rats; Adrb3 expression was differentially regulated.

Conclusion

Both types of chronic stress blunted HPT and BAT responses to cold. Long-term stress effects on noradrenergic and/or hormonal signaling are likely responsible for HPT dysfunction and not the type of chronic stressor.

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Abbreviations

ACTH:

Adrenocorticotropin

Adrb3 :

β3 Adrenergic receptor gene

BAT:

Brown adipose tissue

BWg:

Body weight gain

cAMP:

Cyclic adenosine monophosphate

Cort:

Corticosterone

Cpf:

Control pair-fed

Crh :

Corticotropin-releasing hormone gene

CRH:

Corticotropin-releasing hormone peptide

CVS:

Chronic variable stress

Dio2 :

Deiodinase 2 gene

DIO2:

Deiodinase 2

EPM:

Elevated plus maze

Gr:

Glucocorticoid receptor gene (Nr3c1: nuclear receptor subfamily 3 group C member gene)

HPA:

Hypothalamus–pituitary–adrenal axis

HPT:

Hypothalamus–pituitary–thyroid axis

N:

Naïve

OFT:

Open field test

pCREB:

Phosphorylated cAMP response element-binding protein

PKA:

Protein kinase A

PKAc:

Catalytic subunit of PKA

PVN:

Paraventricular nucleus of the hypothalamus

rRes:

Repeated restraint stress

RT:

Room temperature

RT-PCR:

Reverse transcription polymerase chain reaction

SAS:

Sympathoadrenal system

T3:

3, 3′, 5-Triiodo-l-thyronine

T4:

Thyroxine

Trh :

Thyrotropin-releasing hormone gene

TRH:

Thyrotropin-releasing hormone peptide

TSH:

Thyrotropin

Ucp1 :

Uncoupling protein 1 gene

UCP-1:

Uncoupling protein 1

WAT:

White adipose tissue

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Acknowledgements

The authors acknowledge the technical assistance of M. Gutiérrez-Mariscal, M. Cisneros, F. Romero, R. Rodríguez Bahena, S. Ainsworth and E. López Bustos.

Funding

The present study was supported by UNAM-DGAPA (Grant no. IN213419), CONACYT (Schollarships for graduate studies), CONACYT (Grant no. 284883).

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Author notes

  1. A. Castillo-Campos and A. Mata made equivalent contributions.

Authors and Affiliations

  1. Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, México

    A. Castillo-Campos, A. Gutiérrez-Mata, J.-L. Charli & P. Joseph-Bravo

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  1. A. Castillo-Campos
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  2. A. Gutiérrez-Mata
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Correspondence to P. Joseph-Bravo.

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Maintenance and work with animals followed the Guide for the care and use of laboratory animals (8th ed.), as well as the Mexican norm NOM-062-ZOO-1999. These experiments were approved by the Bioethics Committee of the Institute, approval No. 273 and 318.

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Castillo-Campos, A., Gutiérrez-Mata, A., Charli, JL. et al. Chronic stress inhibits hypothalamus–pituitary–thyroid axis and brown adipose tissue responses to acute cold exposure in male rats. J Endocrinol Invest 44, 713–723 (2021). https://doi.org/10.1007/s40618-020-01328-z

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