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Molecular therapy of obesity and diabetes by a physiological autoregulatory approach

Nature Medicine volume 15, pages 447–454 (2009)Cite this article

Abstract

Hypothalamic brain-derived neurotrophic factor (BDNF) is a key element in the regulation of energy balance. Here we investigated the therapeutic efficacy of BDNF by gene transfer in mouse models of obesity and diabetes. Gene transfer of BDNF led to marked weight loss and alleviation of obesity-associated insulin resistance. To facilitate clinical translation and ensure that BDNF protein expression was appropriately decreased as weight loss progressed, thus preventing cachexia, we developed a molecular autoregulatory system involving a single recombinant adeno-associated virus vector harboring two expression cassettes, one constitutively driving BDNF and the other driving a specific microRNA targeting BDNF. The microRNA element was controlled by a promoter (that controlling the Agrp gene encoding agouti-related peptide) responsive to BDNF-induced physiological changes. Hence, as body weight decreased and agouti-related protein is induced, microRNA expression was activated, inhibiting transgene expression. In contrast to the progressive weight loss associated with a nonregulated approach, this microRNA-approach led to a sustainable plateau of body weight after notable weight loss was achieved. This strategy mimics the body's endogenous physiological feedback mechanisms, thereby resetting the hypothalamic set point to reverse obesity and metabolic syndrome.

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Figure 1: Hypothalamic gene delivery of BDNF leads to weight loss, changes in serum biomarkers and hypothalamic gene expression in wild-type mice fed with NCD.
Figure 2: Hypothalamic gene delivery of BDNF prevents DIO in wild-type mice.
Figure 3: Gene expression profiles of HFD-fed mice.
Figure 4: Autoregulatory BDNF vector to treat db/db mice.
Figure 5: BDNF-induced weight loss is reversible by Cre-loxP–mediated knockout of the transgene.

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Acknowledgements

We thank A. Martin for technical assistance and D. Young, T. Lawlor and D. Fong of the University of Auckland for providing the cDNA encoding HA-tagged BDNF and helpful discussions. The project was supported in part by US National Institutes of Health grant NS44576. E.D.L. is supported by New Zealand Foundation for Research, Science and Technology.

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Authors and Affiliations

  1. Department of Molecular Virology, Cancer Genetics and Neuroscience Program, Immunology and Medical Genetics, and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA

    Lei Cao, En-Ju D Lin, Michael C Cahill, Chuansong Wang, Xianglan Liu & Matthew J During

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  1. Lei Cao
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  2. En-Ju D Lin
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  3. Michael C Cahill
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  4. Chuansong Wang
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Contributions

L.C. developed the idea, designed and conducted most of the experiments and wrote the manuscript. E.-J.D.L. conducted surgery, behavioral tests and contributed to the manuscript. M.C.C. and X.L. assisted with in vivo experiments, behavioral tests and immunohistochemistry. C.W. packaged and purified all vector stocks. M.J.D. is the principal investigator, supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Matthew J During.

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Supplementary Figs. 1–6, Supplementary Table 1 and Supplementary Methods (PDF 646 kb)

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Cao, L., Lin, EJ., Cahill, M. et al. Molecular therapy of obesity and diabetes by a physiological autoregulatory approach. Nat Med 15, 447–454 (2009). https://doi.org/10.1038/nm.1933

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