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

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Abstract
Leptin and BDNF are two protein cytokines known to inhibit food intake. Baoji Xu and colleagues have now shown that leptin-mediated inhibition of food intake is dependent on leptin binding to one set of hypothalamic neurons, which results in neuronal activation of other hypothalamic neurons to increase the dendritic expression of BDNF in those targeted neurons. These results show a new functional link between these two anorexigenic cytokines and how leptin signaling is propagated to regulate food intake. 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.