Neuronal primary cilia integrate peripheral signals with metabolic drives

Abstract

Neuronal primary cilia have recently emerged as important contributors to the central regulation of energy homeostasis. As non-motile, microtubule-based organelles, primary cilia serve as signaling antennae for metabolic status. The impairment of ciliary structure or function can produce ciliopathies for which obesity is a hallmark phenotype and global ablation of cilia induces non-syndromic adiposity in mouse models. This organelle is not only a hub for metabolic signaling, but also for catecholamine neuromodulation that shapes neuronal circuitry in response to sensory input. The objective of this review is to highlight current research investigating the mechanisms of primary cilium-regulated metabolic drives for maintaining energy homeostasis.

Keywords: BBSome; hypothalamus; intraflagellar transport; metabolism; obesity; primary cilium.

FIGURE 1

Distinct mechanism of ciliary protein transport. Structure of primary cilium to highlight distinct ciliary membrane composition in inset. Ciliary trafficking of receptors such as GPCRs involves vesicle budding from the Golgi that docks at the base of the cilium with intraflagellar (IFT)- mediated transportation via anterograde kinesin motors. IFT-A-mediated entry requires TUB like protein 3 (TULP3), a member of the Tubby family of proteins that interacts with the IFT-A core as an effector. The BBSome localizes to the basal body and transition zone and represents a docking point for proteins destined to enter the cilium. The BBSome has also been implicated in the exit of ciliary GPCRs out of the cilium as disruption of its functions leads to accumulation of GPCRs within the cilium. In addition to the BBSome, removal of proteins is mediated by retrograde transport with IFT complexes coupled to dynein motors. The question mark represents the uncertainty regarding how GPCR- associated cAMP and calcium oscillations are transmitted from the cilium to the rest of the neuron.

FIGURE 2

Ciliary-specific signaling in the hypothalamus integrates peripheral nutrient signals with neuronal output and connectivity. Leptin released from the periphery is detected by primary cilia in the hypothalamus. The leptin-melanocortin pathway begins in the ARC with the stimulation of POMC-expressing neurons and the inhibition of AgRP/NPY-expressing neurons. POMC-expressing neurons release α-MSH, which then binds to MC4R to increase satiety. Within the hypothalamus, MCH also regulates energy homeostasis as an orexigenic peptide that is upregulated during fasted states to increase food intake. In addition to the zona incerta, MCH is expressed in the lateral hypothalamus and sends projections locally to the ARC and VMH and to regions such as the brain stem and nucleus accumbens to modulate autonomic and hedonic aspects of food intake.