Diabetes Metab J.  2018 Apr;42(2):117-127. 10.4093/dmj.2018.42.2.117.

Primary Cilia as a Signaling Platform for Control of Energy Metabolism

• Song DK
• Choi JH
• Kim MS

• KMID: 2418703
• DOI: http://doi.org/10.4093/dmj.2018.42.2.117

Abstract

Obesity has become a common healthcare problem worldwide. Cilia are tiny hair-like organelles on the cell surface that are generated and anchored by the basal body. Non-motile primary cilia have been considered to be evolutionary rudiments until a few decades, but they are now considered as important signaling organelles because many receptors, channels, and signaling molecules are highly expressed in primary cilia. A potential role of primary cilia in metabolic regulation and body weight maintenance has been suspected based on rare genetic disorders termed as ciliopathy, such as Bardet-Biedl syndrome and Alström syndrome, which manifest as obesity. Recent studies have demonstrated involvement of cilia-related cellular signaling pathways in transducing metabolic information in hypothalamic neurons and in determining cellular fate during adipose tissue development. In this review, we summarize the current knowledge about cilia and cilia-associated signaling pathways in the regulation of body metabolism.

Keyword

Cilia; Hedgehogs; Metabolism; Obesity; Wnt signaling pathway

MeSH Terms

Adipose Tissue
Alstrom Syndrome
Bardet-Biedl Syndrome
Basal Bodies
Body Weight Maintenance
Cilia*
Delivery of Health Care
Energy Metabolism*
Hedgehogs
Metabolism
Neurons
Obesity
Organelles
Wnt Signaling Pathway

Figure

• 

  Fig. 1 Structure of the primary cilia and intraflagellar transport (IFT) system. A primary cilium is composed of cytoskeleton, called the ciliary axoneme (green), and the ciliary membrane (dark blue line). The basal body acts as a microtubule-organizing center of the ciliary axoneme. The ciliary membrane is enriched for many receptors, ion channels, effector proteins, and transcription factors, which are produced in the cytoplasmic endoplasmic reticulum and transported to the transition zone of cilia via the specialized vesicular trafficking system. The axonemal precursor and ciliary membrane proteins are transported from the base to the tip of the cilia by antegrade IFT (red arrow), which is mediated by the IFT complex B (IFT-B) and motor protein kinesin-2. Retrograde transport (blue arrow) returns turnover products from the tip of the cilia back to the base and is performed by the IFT complex A (IFT-A) with dynein-2 as a motor protein. KAP3, kinesin-associated protein 3; KIF3A, a subunit A of heterotrimeric motor protein kinesin-2; KIF3B/C, a subunit B/C of kinesin 2; ER, endoplasmic reticulum.

• 

  Fig. 2 Signaling pathways related to the primary cilia. (A) Canonical Hedgehog (HH) signaling pathway: under basal condition without HH ligands, the HH receptor Patched (Ptch) inhibits the activity of smoothened (SMO). In this condition, the suppressor of fused (SUFU) binds to the GLI transcription factor and prevents GLI activation. If HH binds to Ptch, SMO migrates to the cilia and activates GLI. GLI leaves cilia and activates the transcription of GLI target genes in the nucleus. (B) Canonical Wnt/β-catenin signaling pathway: without Wnt ligands, β-catenin is ubiquitinated by a destruction complex and degraded by the proteasome. The β-catenin destruction complex is composed of axin, casein kinase-1α (CK-1α), adenomatosis polyposis coli (APC), protein phosphatase 2A (PP2A), and glycogen synthase kinase-3 (GSK-3β). When Wnt ligands bind the Frizzled (Fzd) family receptor and its coreceptor low density lipoprotein receptor-related protein-5/6 (LRP-5/6), the Fzd receptor transmits the signal to inactivate the β-catenin destruction complex. Therefore, β-catenin accumulates in the cytoplasm and translocates to the nucleus where it regulates target gene expression along with the transcriptional coactivator T-cell-specific transcription factor (TCF) family. Dsh, Dishevelled.

• 

  Fig. 3 Potential role of primary cilia in metabolic regulation and body weight control. In hypothalamic neurons, primary cilia may be involved in sensing metabolic signals. In the adipose tissue, primary cilia control the process of adipocyte differentiation by transducing canonical Hedgehog (HH) signaling and Wnt signaling. Moreover, non-canonical HH signaling in the skeletal muscle and brown adipocytes controls glucose and energy metabolism. Therefore, dysfunction or dysgenesis of cilia can lead to obesity and abnormal glucose metabolism.

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