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Modulation of feeding by chronic rAAV expression of a relaxin-3 peptide agonist in rat hypothalamus

Gene Therapy volume 20, pages 703–716 (2013)Cite this article

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Abstract

Relaxin-3 is a neuropeptide that is abundantly expressed by discrete brainstem neuron populations that broadly innervate forebrain areas rich in the relaxin-3 G-protein-coupled-receptor, RXFP3. Acute and subchronic central administration of synthetic relaxin-3 or an RXFP3-selective agonist peptide, R3/I5, increase feeding and body weight in rats. Intrahypothalamic injection of relaxin-3 also increases feeding. In this study, we developed a recombinant adeno-associated virus 1/2 (rAAV1/2) vector that drives expression and constitutive secretion of bioactive R3/I5 and assessed the effect of intrahypothalamic injections on daily food intake and body weight gain in adult male rats over 8 weeks. In vitro testing revealed that the vector rAAV1/2-fibronectin (FIB)-R3/I5 directs the constitutive secretion of bioactive R3/I5 peptide. Bilateral injection of rAAV1/2-FIB-R3/I5 vector into the paraventricular nucleus produced an increase in daily food intake and body weight gain (P<0.01, ∼23%, respectively), relative to control treatment. In a separate cohort of rats, quantitative polymerase chain reaction analysis of hypothalamic mRNA revealed strong expression of R3/I5 transgene at 3 months post-rAAV1/2-FIB-R3/I5 infusion. Levels of mRNA transcripts for the relaxin-3 receptor RXFP3, the hypothalamic ‘feeding’ peptides neuropeptide Y, AgRP and POMC, and the reproductive hormone, GnRH, were all similar to control, whereas vasopressin and oxytocin (OT) mRNA levels were reduced by ∼25% (P=0.051) and ∼50% (P<0.005), respectively, in rAAV1/2-FIB-R3/I5-treated rats (at 12 weeks, n=9/8 rats per group). These data demonstrate for the first time that R3/I5 is effective in modulating feeding in the rat by chronic hypothalamic RXFP3 activation and suggest a potential underlying mechanism involving altered OT signalling. Importantly, there was no desensitization of the feeding response over the treatment period and no apparent deleterious health effects, indicating that targeting the relaxin-3–RXFP3 system may be an effective long-term therapy for eating disorders.

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Acknowledgements

We thank Dr Melanie White, Tania Ferraro and Professor Michael McKinley for technical assistance, Dr Changlu Liu (Johnson & Johnson Pharmaceutical Research and Development LLC, San Diego, CA, USA) for provision of the pCMVSportR3/I5 construct, Professor Thomas McCown (University of North Carolina, Chapel Hill, NC, USA) for the kind gift of the TR-FIB-GFP construct, Dr Michael Mathai (Victoria University, Melbourne, VIC, Australia) for the use of the Echo-MRI Body Composition Analyser and Prof. Geoffrey Tregear for his continuing support. This research was supported by National Health and Medical Research Council of Australia Project Grants 509246 (ALG) and 1005988 (ALG, RADB), and by the Victorian Government Operational Infrastructure Support Programme. DEG is the recipient of Commonwealth Australian Postgraduate Award and GEC was the recipient of a University of Melbourne Research Scholarship. SM and ALG and RADB are recipients of NHMRC (Australia) Training and Research Fellowships, respectively.

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  1. G E Callander

    Present address: 5Current Address: Department of Experimental Medicine and Science, Lund University, Lund, Sweden.,

Authors and Affiliations

  1. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia

    D E Ganella, G E Callander, S Ma, C R Bye, A L Gundlach & R A D Bathgate

  2. Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria, Australia

    D E Ganella, G E Callander & R A D Bathgate

  3. Department of Medicine (Austin Health), The University of Melbourne, Melbourne, Victoria, Australia

    S Ma

  4. Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, Victoria, Australia

    A L Gundlach

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Ganella, D., Callander, G., Ma, S. et al. Modulation of feeding by chronic rAAV expression of a relaxin-3 peptide agonist in rat hypothalamus. Gene Ther 20, 703–716 (2013). https://doi.org/10.1038/gt.2012.83

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