Cold Exposure Increases the Biosynthesis and Proteolytic Processing of Prothyrotropin-Releasing Hormone in the Hypothalamic Paraventricular Nucleus via β-Adrenoreceptors

Abstract

Different physiological conditions affect the biosynthesis and processing of hypophysiotropic proTRH in the hypothalamic paraventricular nucleus, and consequently the output of TRH. Early studies suggest that norepinephrine (NE) mediates the cold-induced activation of the hypothalamic-pituitary-thyroid axis at a central level. However, the specific role of NE on the biosynthesis and processing of proTRH has not been fully investigated. In this study, we found that NE affects gene transcription, protein biosynthesis, and secretion in TRH neurons in vitro; these changes were coupled with an up-regulation of prohormone convertase enzymes (PC) 1/3 and PC2. In vivo, NE is the main mediator of the cold-induced activation of the hypothalamic-pituitary-thyroid axis at the hypothalamic level, in which it potently stimulates the biosynthesis and proteolytic processing of proTRH through a coordinated up-regulation of the PCs. This activation occurs via beta-adrenoreceptors and phosphorylated cAMP response element binding signaling. In contrast, alpha-adrenoreceptors regulate TRH secretion but not proTRH biosynthesis and processing. Therefore, this study provides novel information on the molecular mechanisms of control of hypophysiotropic TRH biosynthesis.

Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing

“…1) Because rats share with humans many characteristics of obesity physiology (24), they are considered to be an excellent model to study obesity physiology (17,25,26). 2) We have extensively characterized this model for energy balance studies as well as gene and peptide analyses, including prohormone processing (16,18,19,(27)(28)(29). 3) POMC processing was established in the rat (30 -33), and we showed for the first time the changes in POMC processing in the rat ARC under nutritional changes (16).…”

Pro-TRH and pro-CRF expression in paraventricular nucleus of small litter-reared fasted adult rats

“…PVN TRHergic cells are innervated by ascending catecholaminergic neurons from the brainstem (Cunningham & Sawchenko 1988, Füzesi et al 2009). Noradrenaline (NA) is an upregulator of hypophysiotropic proTRH expression (Uribe et al 1993, Perello et al 2007. Importantly, brain NA concentrations in early-overfed animals are low (Seidler et al 1990), and the binding of adrenergic receptors in PVN is reduced in diet-induced obese rats (Levin 1996).…”

Phosphorylated Cyclic-AMP-Response Element-Binding Protein and Thyroid Hormone Receptor Have Independent Response Elements in the Rat Thyrotropin-Releasing Hormone Promoter: An Analysis in Hypothalamic Cells

“…The rapid increase in PVN-TRH mRNA levels by cold exposure is mimicked in primary cultures of rat fetal hypothalamic cells by noradrenaline [7,8], the mediator of the cold response [9], as well as by protein kinase A activation [7,10]. An increase in intracellular cAMP levels leads to dissociation and nuclear translocation of protein kinase A catalytic subunit, with rapid phosphorylation of the cAMP response element-binding protein (CREB), which binds to cAMP response elements (CREs) in the DNA and to the CREB-binding protein, activating transcription [11,12].…”