Leptin Elongates Hypothalamic Neuronal Cilia via Transcriptional Regulation and Actin Destabilization

Terminally differentiated neurons have a single, primary cilium. The primary cilia of hypothalamic neurons play a critical role in sensing metabolic signals. We recently showed that mice with leptin deficiency or resistance have shorter cilia in the hypothalamic neurons, and leptin treatment elongates cilia in hypothalamic neurons. Here, we investigated the molecular mechanisms by which leptin controls ciliary length in hypothalamic neurons. In N1 hypothalamic neuronal cells, leptin treatment increased the expression of intraflagellar transport proteins. These effects occurred via phosphatase and tensin homolog/glycogen synthase kinase-3β-mediated inhibition of the transcriptional factor RFX1. Actin filament dynamics were also involved in leptin-promoted ciliary elongation. Both leptin and cytochalasin-D treatment induced F-actin disruption and cilium elongation in hypothalamic neurons that was completely abrogated by co-treatment with the F-actin polymerizer phalloidin. Our findings suggest that leptin elongates hypothalamic neuronal cilia by stimulating the production of intraflagellar transport proteins and destabilizing actin filaments. The primary cilia in hypothalamic neurons are important for sensing metabolic signals. Leptin promotes cilium growth in the hypothalamic neuronal cells by increasing intraflagellar transport gene transcription and F-actin rearrangement. Leptin is an important regulator of ciliary length in hypothalamic neurons. Dynamic regulation of hypothalamic neuron ciliary lengths represents a novel strategy by which leptin regulates energy balance.