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Hypothalamic delivery of doxycycline-inducible leptin gene allows for reversible transgene expression and physiological responses

Gene Therapy volume 9, pages 1492–1499 (2002)Cite this article

Abstract

Our purpose was to incorporate regulation into the recombinant adeno-associated virus encoding leptin by introducing a tet-inducible promotor. This system, TET-Ob, allows for control of leptin gene expression via doxycycline in drinking water. F344XBN rats (aged 4 months) were given a hypothalamic injection of TET-Ob or control virus. During 34 days of doxycycline (doxy) administration to all rats (STAGE 1), TET-Ob rats gained 50.7% less mass, ate 10.4% less food, and had a 77.5% reduction in serum leptin as compared with controls. Doxy was then withdrawn from half of the TET-Ob rats for 32 days (TET-Ob-OFF), while half continued to receive doxy (TET-Ob-ON) (stage 2). During stage 2, TET-Ob-ON rats gained 44.8% less mass than TET-Ob-OFF and ate significantly less food than both TET-Ob-OFF and controls. Serum leptin increased to 83.4% of control values in TET-Ob-OFF, but remained very low in the in TET-Ob-ON. At death, visceral adiposity was 14.5% of controls in TET-Ob-ON animals, but had risen to 76.9% of controls in TET-Ob-OFF. A reversible increase in both leptin signal transduction in the hypothalamus and uncoupling protein expression in brown adipose was recorded. This system allows for more precise regulation of gene therapy-mediated fat loss.

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Acknowledgements

This work was supported by the Medical Research Service of the Department of Veterans Affairs and National Institute on Aging Grant AG-17047.

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Authors and Affiliations

  1. Department of Veterans Affairs Medical Center, Geriatric Research, Education and Clinical Center, Gainesville, FL, USA

    J Wilsey, E W Shek, M K Matheny & P J Scarpace

  2. Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA

    J Wilsey, E W Shek, M K Matheny & P J Scarpace

  3. Department of Molecular Genetics, University of Florida College of Medicine, Gainesville, FL, USA

    S Zolotukhin & V Prima

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  1. J Wilsey
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Wilsey, J., Zolotukhin, S., Prima, V. et al. Hypothalamic delivery of doxycycline-inducible leptin gene allows for reversible transgene expression and physiological responses. Gene Ther 9, 1492–1499 (2002). https://doi.org/10.1038/sj.gt.3301835

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  • DOI: https://doi.org/10.1038/sj.gt.3301835

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