Leptin Elongates Hypothalamic Neuronal Cilia via Transcriptional Regulation and Actin Destabilization

Gil Myoung Kang,Yu Mi Han,Hyuk Whan Ko,Joon Kim,Byung Chul Oh,Ijoo Kwon,Min-Seon Kim

doi:10.1074/jbc.m115.639468

Abstract

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.

Highlights

The primary cilia in hypothalamic neurons are important for sensing metabolic signals
Leptin increased the ciliary lengths in N1 hypothalamic neuronal cells and primary cultures of hypothalamic neurons
Leptin did not cause any ciliary changes in RPE-1 cells, which are commonly used for ciliary studies [21, 24]

Summary

Background

The primary cilia in hypothalamic neurons are important for sensing metabolic signals. 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-3␤-mediated inhibition of the transcriptional factor RFX1. Artificially inducing the short phenotype in the hypothalamic cilia of adult mice leads to increased food intake and body weight and an impaired anorexigenic response to physiological satiety signals, such as leptin, insulin, and glucose [13]. These data suggest that ciliary length in hypothalamic neurons is important for regulating appetite and body weight. We investigated the molecular mechanisms by which leptin regulates the lengths of the primary cilia in hypothalamic neurons

Experimental Procedures

Results

Discussion