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 () and Min-Seon Kim ()
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Chan Hee Lee: University of Ulsan College of Medicine
Do Kyeong Song: Asan Medical Center and University of Ulsan College of Medicine
Chae Beom Park: Asan Medical Center and University of Ulsan College of Medicine
Jeewon Choi: Korea Advanced Institute of Science and Technology
Gil Myoung Kang: University of Ulsan College of Medicine
Sung Hoon Shin: Asan Medical Center and University of Ulsan College of Medicine
Ijoo Kwon: University of Ulsan College of Medicine
Soyoung Park: Children’s Hospital Los Angeles, University of Southern California
Seongjun Kim: Asan Medical Center and University of Ulsan College of Medicine
Ji Ye Kim: University of Ulsan College of Medicine
Hong Dugu: Asan Medical Center and University of Ulsan College of Medicine
Jae Woo Park: Asan Medical Center and University of Ulsan College of Medicine
Jong Han Choi: Asan Medical Center and University of Ulsan College of Medicine
Se Hee Min: Asan Medical Center and University of Ulsan College of Medicine
Jong-Woo Sohn: Korea Advanced Institute of Science and Technology
Min-Seon Kim: University of Ulsan College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19638-4

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