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

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 und...

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Veröffentlicht in:Nature communications 2020-11, Vol.11 (1), p.5772-5772, Article 5772
Hauptverfasser: Lee, Chan Hee, Song, Do Kyeong, Park, Chae Beom, Choi, Jeewon, Kang, Gil Myoung, Shin, Sung Hoon, Kwon, Ijoo, Park, Soyoung, Kim, Seongjun, Kim, Ji Ye, Dugu, Hong, Park, Jae Woo, Choi, Jong Han, Min, Se Hee, Sohn, Jong-Woo, Kim, Min-Seon
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Sprache:eng
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Zusammenfassung: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. Ciliary defects and obesity has been associated, but the underlying mechanism is unclear. Here, the authors show that inhibition of ciliogenesis in POMC neurons during development results in lysosomal protein degradation-dependent axonal disruption and adult obesity in mice.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-19638-4