Vol.:(0123456789) 1 3 Journal of Endocrinological Investigation https://doi.org/10.1007/s40618-020-01328-z ORIGINAL ARTICLE Chronic stress inhibits hypothalamus–pituitary–thyroid axis and brown adipose tissue responses to acute cold exposure in male rats A. Castillo‑Campos 1  · A. Gutiérrez‑Mata 1  · J.‑L. Charli 1  · P. Joseph‑Bravo 1 Received: 26 December 2019 / Accepted: 5 June 2020 © Italian Society of Endocrinology (SIE) 2020 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 diferentially regulated. Conclusion Both types of chronic stress blunted HPT and BAT responses to cold. Long-term stress efects on noradrenergic and/or hormonal signaling are likely responsible for HPT dysfunction and not the type of chronic stressor. Keywords Thyrotropin-releasing hormone · Brown adipose tissue · Hypothalamus–pituitary–thyroid · Hypothalamus– pituitary–adrenal · Restraint · Chronic variable stress · Cold stress 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 feld test pCREB Phosphorylated cAMP response element-bind- ing protein PKA Protein kinase A PKAc Catalytic subunit of PKA A. Castillo-Campos and A. Mata made equivalent contributions. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40618-020-01328-z) contains supplementary material, which is available to authorized users. * P. Joseph-Bravo joseph@ibt.unam.mx 1 Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, México