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Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin

Abstract

Mutations in the Bdnf gene, which produces transcripts with either short or long 3′ untranslated regions (3′ UTRs), cause human obesity; however, the precise role of brain-derived neurotrophic factor (BDNF) in the regulation of energy balance is unknown. Here we show the relationship between Bdnf mRNA with a long 3′ UTR (long 3′ UTR Bdnf mRNA), leptin, neuronal activation and body weight. We found that long 3′ UTR Bdnf mRNA was enriched in the dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3′ UTR developed severe hyperphagic obesity, which was completely reversed by viral expression of long 3′ UTR Bdnf mRNA in the hypothalamus. In these mice, the ability of leptin to activate hypothalamic neurons and inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process.

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Figure 1: Mice lacking long 3′ UTR Bdnf mRNA show severe hyperphagic obesity.
Figure 2: Viral expression of long 3′ UTR Bdnf mRNA in the VMH corrects the obesity syndrome in Bdnfklox/klox mice.
Figure 3: Insulin stimulates local translation of transcripts containing the long Bdnf 3′ UTR in the dendrites of hypothalamic neurons.
Figure 4: Leptin activates hypothalamic BDNF-expressing neurons through network activity.
Figure 5: Leptin normally activates LepRb in Bdnfklox/klox mice.
Figure 6: Leptin-induced neuronal activation is impaired in Bdnfklox/klox mice.

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Acknowledgements

This work was supported by the grants from the US National Institutes of Health to B.X. (R01 DK089237, R21 DK081008 and R01 NS050596), E.G.W. (F30 DK084717) and F.V. (F31 NS060453) and from the American Diabetes Association to B.X. (7-07-RA-183).

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Contributions

G.-Y.L. performed experiments addressing the obesity syndrome, local protein synthesis, viral BDNF expression, coexpression of BDNF and TrkB with the leptin receptor, STAT3 activation and c-Fos induction. J.J.A. analyzed Bdnf mRNA subcellular localization and gene expression. K.G. characterized the obesity phenotype of the Bdnfklox/klox mice. E.G.W. created viral constructs and helped G.-Y.L. with stereotaxic AAV microinjection. F.V. generated the reporter constructs for local BDNF synthesis. K.R.J. provided the Bdnfklox/klox mouse strain. B.X. supervised the project. B.X. and G.-Y.L. wrote the manuscript.

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Correspondence to Baoji Xu.

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Competing interests

B.X., J.J.A. and E.G.W. are co-inventors on a patent application filed by Georgetown University that is related to the technology described in this paper.

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Liao, GY., An, J., Gharami, K. et al. Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin. Nat Med 18, 564–571 (2012). https://doi.org/10.1038/nm.2687

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