Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus

Chan Hee Lee, Do Kyeong Song, Chae Beom Park, Jeewon Choi, Gil Myoung Kang, Sung Hoon Shin, Ijoo Kwon, Soyoung Park, Seongjun Kim, Ji Ye Kim, Hong Dugu, Jae Woo Park, Jong Han Choi, Se Hee Min, Jong Woo Sohn, Min Seon Kim

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish
Article number5772
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - Dec 2020

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