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.
Highlights
Hypothalamic neurons including proopiomelanocortin (POMC)-producing neurons regulate body weights
Aberrant ciliogenesis was confirmed by staining cilia with an antibody against adenylyl cyclase-3 (AC3) as it is enriched in primary cilia of the central nervous system[32]
Stunted cilia were observed in the tdTomato-labeled POMC neurons of POMC-cre/ERT2;;IFT88f/f;; tdTomato mice but ciliogenesis in non-POMC neurons was unaltered (Fig. 1b)
Summary
Hypothalamic neurons including proopiomelanocortin (POMC)-producing neurons regulate body weights. Our findings reveal a mechanism of early life programming of adult adiposity, which is mediated by primary cilia in developing hypothalamic neurons. Human epidemiology studies have demonstrated a strong association between maternal nutrition/birth weights and the adulthood risks of obesity-related medical comorbidity[2,3] In rodent experiments, both overnutrition and undernutrition during gestation and lactation predispose the offspring to obesity and metabolic disorders in later life[4,5]. Most mammalian cells including hypothalamic neurons, have tiny hair-like primary cilia on their cell surfaces[13,14] To generate these cilia, ciliary structural proteins are transported to the ciliary tip via a process known as antegrade intraflagellar transport (IFT), which is mediated by kinesin-II motor and IFT complex B15. The role of the primary cilia during hypothalamic development remains elusive
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
