Thyroid hormone and vitamin D regulate VGF expression and promoter activity.

Jo E Lewis,Dana Wilson,Perry Barrett,John M Brameld,Francis J P Ebling,Phil Hill,Preeti H Jethwa

doi:10.1530/jme-15-0224

Abstract

The Siberian hamster (Phodopus sungorus) survives winter by decreasing food intake and catabolizing abdominal fat reserves, resulting in a sustained, profound loss of body weight. Hypothalamic tanycytes are pivotal for this process. In these cells, short-winter photoperiods upregulate deiodinase 3, an enzyme that regulates thyroid hormone availability, and downregulate genes encoding components of retinoic acid (RA) uptake and signaling. The aim of the current studies was to identify mechanisms by which seasonal changes in thyroid hormone and RA signaling from tanycytes might ultimately regulate appetite and energy expenditure. proVGF is one of the most abundant peptides in the mammalian brain, and studies have suggested a role for VGF-derived peptides in the photoperiodic regulation of body weight in the Siberian hamster. In silico studies identified possible thyroid and vitamin D response elements in the VGF promoter. Using the human neuroblastoma SH-SY5Y cell line, we demonstrate that RA increases endogenous VGF expression (P<0.05) and VGF promoter activity (P<0.0001). Similarly, treatment with 1,25-dihydroxyvitamin D3 increased endogenous VGF mRNA expression (P<0.05) and VGF promoter activity (P<0.0001), whereas triiodothyronine (T3) decreased both (P<0.01 and P<0.0001). Finally, intra-hypothalamic administration of T3 blocked the short day-induced increase in VGF expression in the dorsomedial posterior arcuate nucleus of Siberian hamsters. Thus, we conclude that VGF expression is a likely target of photoperiod-induced changes in tanycyte-derived signals and is potentially a regulator of seasonal changes in appetite and energy expenditure.

Highlights

The Siberian hamster (Phodopus sungorus) has been increasingly used to investigate hypothalamic mechanisms regulating energy homeostasis due to its natural seasonal cycle of appetite, energy expenditure, and body weight (Ebling 2014)
We previously demonstrated that thyroid hormone (T3) availability in the hypothalamus was likely to be reduced in hamsters in short-day photoperiod (SD), due to increase in deiodinase 3 (DIO3) expression (Barrett et al 2007, Murphy et al 2012), while changes in vitamin D production have previously been associated with photoperiod, in the human kidney and skin (Webb et al 1988, Holick 1995)
Using the human neuroblastoma SH-SY5Y cell line, we have demonstrated that retinoic acid (RA) and nerve growth factor (NGF) increase both endogenous VGF mRNA expression and VGF promoter activity

Summary

Introduction

The Siberian hamster (Phodopus sungorus) has been increasingly used to investigate hypothalamic mechanisms regulating energy homeostasis due to its natural seasonal cycle of appetite, energy expenditure, and body weight (Ebling 2014). These hamsters naturally become obese in the summer long-day photoperiod (LD), but enter a catabolic state during winter short-day photoperiod (SD) where they reduce their food intake and catabolize intra-abdominal fat reserves, subsequently losing up to a third of their body weight (Bartness et al 1989, Klingenspor et al 1996, Mercer et al 2001). The major question arises as to how seasonal changes in thyroid hormone and RA signaling from tanycytes to hypothalamic neurons regulate appetite and energy expenditure

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