Photoperiodic changes in adiposity increase sensitivity of female Siberian hamsters to systemic VGF derived peptide TLQP-21.

Carlo Lisci,Tyler J Stevenson,Maxine Fowler,Gian-Luca Ferri,Preeti H Jethwa,Hayley J Marshall,Zoe C T R Daniel,Chloe Monnier,Jo E Lewis,Cristina Cocco,Francis J P Ebling

doi:10.1371/journal.pone.0221517

Abstract

TLQP-21, a peptide encoded by the highly conserved vgf gene, is expressed in neuroendocrine cells and has been the most prominent VGF-derived peptide studied in relation to control of energy balance. The recent discovery that TLQP-21 is the natural agonist for the complement 3a receptor 1 (C3aR1) has revived interest in this peptide as a potential drug target for obesity. We have investigated its function in Siberian hamsters (Phodopus sungorus), a rodent that displays natural seasonal changes in body weight and adiposity as an adaptation to survive winter. We have previously shown that intracerebroventricular administration of TLQP-21 reduced food intake and body weight in hamsters in their long-day fat state. The aim of our current study was to determine the systemic actions of TLQP-21 on food intake, energy expenditure and body weight, and to establish whether adiposity affected these responses. Peripheral infusion of TLQP-21 (1mg/kg/day for 7 days) in lean hamsters exposed to short photoperiods (SP) reduced cumulative food intake in the home cage (p<0.05), and intake when measured in metabolic cages (P<0.01). Energy expenditure was significantly increased (p<0.001) by TLQP-21 infusion, this was associated with a significant increase in uncoupling protein 1 mRNA in brown adipose tissue (BAT) (p<0.05), and body weight was significantly reduced (p<0.05). These effects of systemic TLQP-21 treatment were not observed in hamsters exposed to long photoperiod (LP) with a fat phenotype. C3aR1 mRNA and protein were abundantly expressed in the hypothalamus, brown and white adipose tissue in hamsters, but changes in expression cannot explain the differential response to TLQP-21 in lean and fat hamsters.

Highlights

Siberian hamsters (Phodopus sungorus) undergo natural seasonal cycles of adiposity
Interest in TLQP-21 has recently been renewed following the discovery of a cognate receptor complement 3a receptor 1 (C3aR1), which has been implicated in a number of diseases including obesity and diabetes [25]
C3aR1 mRNA expression has been observed in brown adipose tissue (BAT), muscle, liver and brain, and this expression is altered by high fat feeding [25]

Summary

Introduction

Siberian hamsters (Phodopus sungorus) undergo natural seasonal cycles of adiposity. They are hyperphagic and accumulate large fat reserves in the summer under long photoperiods (LP), but in response to short (winter) photoperiods (SP) they enter a catabolic state where they reduce their food intake, and catabolize intra-abdominal fat reserves, subsequently reducing body weight by a third [1, 2]. We have shown that thyroid hormones, namely tri-iodothyronine, decrease the expression of vgf mRNA in vitro and in vivo in hamsters exposed to SP [5]. Switching from SP to LP results in rapid decreases in vgf mRNA expression in the dmpARC ahead of body weight increases [6]. We have shown that over-expression of vgf in the hypothalamus using a rAAV strategy increases energy expenditure and reduces body weight gain in hamsters in LP [7], consistent with our previous observations that infusion of TLQP-21 into the hypothalamus exerts catabolic actions [8]

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