Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Patrick N Stoney,Peter Mccaffery,Diana Rodrigues,Gisela Helfer,Peter J Morgan

doi:10.1002/glia.22938

Abstract

Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)‐synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA‐responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1‐expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus. GLIA 2016;64:425–439

Highlights

Thyroid hormones (TH) act to control gene expression by binding and activating specific nuclear receptor family transcription factors
Peripheral Administration of T3 Upregulates Hypothalamic retinaldehyde dehydrogenase 1 (Raldh1) Expression Thyroid hormone signalling in the hypothalamus is thought to play a crucial role in the control of energy balance, but little is known about its direct targets in the hypothalamus
Deiodinase 3 (Dio3) was strongly upregulated in the hypothalamus of T3-treated rats (Fig. 1A), confirming that peripheral administration of T3 increased hypothalamic T3 and that the time between administration and dissection was sufficient for alterations in hypothalamic gene expression

Summary

Introduction

Thyroid hormones (TH) act to control gene expression by binding and activating specific nuclear receptor family transcription factors. Acute and chronic administration of low doses of T3 has been shown to increase feeding without affecting energy expenditure (Kong et al, 2004) These observations suggest that TH has central, as well as peripheral effects on the regulation of feeding behavior and metabolic states. The importance of TH signalling in the hypothalamus is highlighted in the regulation of energy balance of seasonal animals (Barrett et al, 2007). This highly conserved pathway is considered to be the basis of long-term changes in energy balance, growth and reproduction, in birds and mammals. In Siberian hamsters, hypothalamic implants releasing T3 promote long day-like (i.e. summer-like) reproductive and body weight responses

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