Transcription Factor TonEBP Stimulates Hyperosmolality-Dependent Arginine Vasopressin Gene Expression in the Mouse Hypothalamus.

Dong Hee Kim,Jin Woo Kim,Kwang Kon Kim,Jin Kwon Jeong,Byung Ju Lee,Tae Hwan Lee,Jeong Woo Park,Hyejin Eom

doi:10.3389/fendo.2021.627343

Abstract

The hypothalamic neuroendocrine system is strongly implicated in body energy homeostasis. In particular, the degree of production and release of arginine vasopressin (AVP) in the hypothalamus is affected by plasma osmolality, and that hypothalamic AVP is responsible for thirst and osmolality-dependent water and metabolic balance. However, the osmolality-responsive intracellular mechanism within AVP cells that regulates AVP synthesis is not clearly understood. Here, we report a role for tonicity-responsive enhancer binding protein (TonEBP), a transcription factor sensitive to cellular tonicity, in regulating osmosensitive hypothalamic AVP gene transcription. Our immunohistochemical work shows that hypothalamic AVP cellular activity, as recognized by c-fos, was enhanced in parallel with an elevation in TonEBP expression within AVP cells following water deprivation. Interestingly, our in vitro investigations found a synchronized pattern of TonEBP and AVP gene expression in response to osmotic stress. Those results indicate a positive correlation between hypothalamic TonEBP and AVP production during dehydration. Promoter and chromatin immunoprecipitation assays confirmed that TonEBP can bind directly to conserved binding motifs in the 5’-flanking promoter regions of the AVP gene. Furthermore, dehydration- and TonEBP-mediated hypothalamic AVP gene activation was reduced in TonEBP haploinsufficiency mice, compared with wild TonEBP homozygote animals. Therefore, our result support the idea that TonEBP is directly necessary, at least in part, for the elevation of AVP transcription in dehydration conditions. Additionally, dehydration-induced reductions in body weight were rescued in TonEBP haploinsufficiency mice. Altogether, our results demonstrate an intracellular machinery within hypothalamic AVP cells that is responsible for dehydration-induced AVP synthesis.

Highlights

The fluid and metabolic systems are reciprocally interconnected, and body fluid status, i.e., hydration or dehydration, strongly influences a broad spectrum of metabolic parameters, including food intake, weight gain, and energy expenditure, in both human and non-human species [1,2,3,4,5]
The activity of arginine vasopressin (AVP) cells in both regions was enhanced by water-deprived hyperosmolality compared with euhydrated control mice
Double IHC was performed to determine whether hyperosmolalitydependent production of tonicity-responsive enhancer binding protein (TonEBP) occurs in hypothalamic AVP cells (Figure 2)

Summary

Introduction

The fluid and metabolic systems are reciprocally interconnected, and body fluid status, i.e., hydration or dehydration, strongly influences a broad spectrum of metabolic parameters, including food intake, weight gain, and energy expenditure, in both human and non-human species [1,2,3,4,5]. Synaptic fibers from the SFO and OVLT project into the hypothalamic nuclei, such as the paraventricular (PVN) and supraoptic nuclei (SON) [8, 10, 13,14,15,16] Those hypothalamic nuclei have been recognized as the forebrain metabolic center; they integrate central and peripheral water and metabolic information and regulate neuroendocrine outputs, including the production and release of arginine vasopressin (AVP), in response to the body’s needs. SFO excitatory neurons predict the body’s need for fluid homeostasis following eating and drinking and activate the release of hypothalamic AVP to induce thirst-dependent drinking behavior in awake animals before any change in blood osmolality can occur [8, 10]. The hypothalamic AVP system plays a central role in both intero-sensory regulation and the rapid anticipatory drinking response that promotes fluid homeostasis [3]

Methods

Results

Conclusion