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

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.

Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons

“…Abnormalities in brain development are a characteristic feature of many ciliopathies, highlighting the critical role of cilia in the nervous system (Guemez-Gamboa et al, 2014; Louvi and Grove, 2011; Valente et al, 2014; Youn and Han, 2018). Cilia have now been implicated in neurogenesis, neuronal migration, and establishment of synaptic connectivity during development (Baudoin et al, 2012; Chizhikov et al, 2007; Guo et al, 2017; Guo et al, 2019; Higginbotham et al, 2012; Higginbotham et al, 2013; Lee et al, 2020; Spassky et al, 2008; Willaredt et al, 2008). Intriguingly, cilia along with their complex signaling machinery are retained on mature neurons (Arellano et al, 2012; Guadiana et al, 2016; Sterpka and Chen, 2018), but whether ciliary signaling dynamically modulates mature neuronal properties has not been explored.…”

Hypothalamic primary cilium: A hub for metabolic homeostasis

“…Several recent studies have revealed the distinct roles of hypothalamic primary cilia in controlling energy balance (Fig. 3) [41,61,62,64,77]. Although the functional importance of cilia has been determined, studies are needed to further reveal and to gain full understanding of the molecular composition of neuronal cilia and their precise roles in modulating energy homeostasis, primarily by determining the distinct roles that hypothalamic primary cilia play in different neurons.…”

“…Moreover, given that cilia biogenic genes such as Ift88 have ciliaindependent roles in tissue development, direct evidence that defects in ciliary formation per se are necessary for acquisition of a pathological phenotype is still needed. Additionally, since primary cilia have been known to contribute to neural development, it would be reasonable to examine whether neuronal cilia influence the formation of the neuronal circuit [64,83,84]. In summary, studies of hypothalamic primary cilia offer great potential to gain understanding of other aspects of energy homeostasis regulation through the central nervous system and possibly provide a new strategy to overcome metabolic disorders.…”

“…A recent study showed that inhibition of ciliogenesis in developing POMC neurons, which was realized by depleting Kif3a or Ift88, led to adulthood obesity in mice [64]; these mice showed disruption of axonal projections through impaired lysosomal protein degradation in POMC neurons. In contrast, ciliary deletion in adult POMC neurons using tamoxifen-inducible cre did not lead to significant changes in body weight, fat mass, or lean mass, suggesting that primary cilia in adult POMC neurons have a minimal role in the regulation of energy balance.…”

Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons

“…Abnormalities in brain development are a characteristic feature of many ciliopathies, highlighting the critical role of cilia in the nervous system (Guemez-Gamboa et al, 2014;Louvi and Grove, 2011;Valente et al, 2014;Youn and Han, 2018). Cilia have now been implicated in neurogenesis, neuronal migration, and establishment of synaptic connectivity during development (Baudoin et al, 2012;Chizhikov et al, 2007;Guo et al, 2017;Guo et al, 2019;Higginbotham et al, 2012;Higginbotham et al, 2013;Lee et al, 2020;Spassky et al, 2008;Willaredt et al, 2008). Intriguingly, cilia along with their complex signaling machinery are retained on mature neurons (Arellano et al, 2012;Guadiana et al, 2016;Sterpka and Chen, 2018), but whether ciliary signaling dynamically modulates mature neuronal properties has not been explored.…”