Hypothalamic neurons including proopiomelanocortin (POMC)-producing neurons regulate body weights. The non-motile primary cilium is a critical sensory organelle on the cell surface. An association between ciliary defects and obesity has been suggested, but the underlying mechanisms are not fully understood. Here we show that inhibition of ciliogenesis in POMC-expressing developing hypothalamic neurons, by depleting ciliogenic genes IFT88 and KIF3A, leads to adulthood obesity in mice. In contrast, adult-onset ciliary dysgenesis in POMC neurons causes no significant change in adiposity. In developing POMC neurons, abnormal cilia formation disrupts axonal projections through impaired lysosomal protein degradation. Notably, maternal nutrition and postnatal leptin surge have a profound impact on ciliogenesis in the hypothalamus of neonatal mice; through these effects they critically modulate the organization of hypothalamic feeding circuits. Our findings reveal a mechanism of early life programming of adult adiposity, which is mediated by primary cilia in developing hypothalamic neurons.
Bibliographical noteFunding Information:
We thank Dr. Keetae Kim for generating the IFT88 shRNA-AAV plasmids and the Scientific Publications Team at Asan Medical Center and Editage (www.editage.co.kr) for the editorial assistance in preparing this manuscript. This study was supported by grants from the Samsung Science & Technology Foundation (SSTF-BA140-215) and National Research Foundation of Korea funded by the Korean government (2020R1A2C300484311 to M.-S.K. and 2019R1A2C2005161 to J.-W.S.).
© 2020, The Author(s).