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http://dx.doi.org/10.5483/BMBRep.2015.48.12.229

Primary cilia in energy balance signaling and metabolic disorder  

Lee, Hankyu (College of Pharmacy, Dongguk University)
Song, Jieun (College of Pharmacy, Dongguk University)
Jung, Joo Hyun (College of Pharmacy, Dongguk University)
Ko, Hyuk Wan (College of Pharmacy, Dongguk University)
Publication Information
BMB Reports / v.48, no.12, 2015 , pp. 647-654 More about this Journal
Abstract
Energy homeostasis in our body system is maintained by balancing the intake and expenditure of energy. Excessive accumulation of fat by disrupting the balance system causes overweight and obesity, which are increasingly becoming global health concerns. Understanding the pathogenesis of obesity focused on studying the genes related to familial types of obesity. Recently, a rare human genetic disorder, ciliopathy, links the role for genes regulating structure and function of a cellular organelle, the primary cilium, to metabolic disorder, obesity and type II diabetes. Primary cilia are microtubule based hair-like membranous structures, lacking motility and functions such as sensing the environmental cues, and transducing extracellular signals within the cells. Interestingly, the subclass of ciliopathies, such as Bardet-Biedle and Alström syndrome, manifest obesity and type II diabetes in human and mouse model systems. Moreover, studies on genetic mouse model system indicate that more ciliary genes affect energy homeostasis through multiple regulatory steps such as central and peripheral actions of leptin and insulin. In this review, we discuss the latest findings in primary cilia and metabolic disorders, and propose the possible interaction between primary cilia and the leptin and insulin signal pathways which might enhance our understanding of the unambiguous link of a cell's antenna to obesity and type II diabetes.
Keywords
Ciliogenesis; Ciliopathy; Insulin; Leptin; Obesity; Primary cilia;
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1 Kim JC, Ou YY, Badano JL et al (2005) MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis. J Cell Sci 118, 1007-1020   DOI
2 Naaz A, Holsberger DR, Iwamoto GA, Nelson A, Kiyokawa H and Cooke PS (2004) Loss of cyclin-dependent kinase inhibitors produces adipocyte hyperplasia and obesity. FASEB J 18, 1925-1927
3 Marion V, Mockel A, De Melo C et al (2012) BBS-induced ciliary defect enhances adipogenesis, causing paradoxical higher-insulin sensitivity, glucose usage, and decreased inflammatory response. Cell Metab 16, 363-377   DOI
4 Abelson P and Kennedy D (2004) The obesity epidemic. Science 304, 1413   DOI
5 Sen Gupta P, Prodromou NV and Chapple JP (2009) Can faulty antennae increase adiposity? The link between cilia proteins and obesity. J Endocrinol 203, 327-336   DOI
6 Spiegelman BM and Flier JS (2001) Obesity and the regulation of energy balance. Cell 104, 531-543   DOI
7 Meyre D, Delplanque J, Chevre JC et al (2009) Genomewide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet 41, 157-159   DOI
8 Speliotes EK, Willer CJ, Berndt SI et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42, 937-948   DOI
9 Hildebrandt F, Benzing T and Katsanis N (2011) Ciliopathies. N Engl J Med 364, 1533-1543   DOI
10 Ko HW (2012) The primary cilium as a multiple cellular signaling scaffold in development and disease. BMB Rep 45, 427-432   DOI
11 Badano JL, Mitsuma N, Beales PL and Katsanis N (2006) The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7, 125-148   DOI
12 Mutch DM and Clement K (2006) Unraveling the genetics of human obesity. PLoS Genet 2, e188   DOI
13 Reiter JF and Mostov K (2006) Vesicle transport, cilium formation, and membrane specialization: the origins of a sensory organelle. Proc Natl Acad Sci U S A 103, 18383-18384   DOI
14 Reiter JF, Blacque OE and Leroux MR (2012) The base of the cilium: roles for transition fibres and the transition zone in ciliary formation, maintenance and compartmentalization. EMBO Rep 13, 608-618   DOI
15 Zaghloul NA and Katsanis N (2010) Functional modules, mutational load and human genetic disease. Trends Genet 26, 168-176   DOI
16 Ishikawa H and Marshall WF (2011) Ciliogenesis: building the cell's antenna. Nat Rev Mol Cell Biol 12, 222-234   DOI
17 Veleri S, Manjunath SH, Fariss RN et al (2014) Ciliopathyassociated gene Cc2d2a promotes assembly of subdistal appendages on the mother centriole during cilia biogenesis. Nat Commun 5, 4207   DOI
18 Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS et al (2011) A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 43, 776-784   DOI
19 Sang L, Miller JJ, Corbit KC et al (2011) Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145, 513-528   DOI
20 Laurence JZ and Moon RC (1995) Four cases of "retinitis pigmentosa" occurring in the same family, and accompanied by general imperfections of development. 1866. Obes Res 3, 400-403   DOI
21 M’Hamdi O, Ouertani I and Chaabouni-Bouhamed H (2014) Update on the genetics of bardet-biedl syndrome. Mol Syndromol 5, 51-56   DOI
22 Ansley SJ, Badano JL, Blacque OE et al (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425, 628-633   DOI
23 Nachury MV, Loktev AV, Zhang Q et al (2007) A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201-1213   DOI
24 Alstrom CH, Hallgren B, Nilsson LB and Asander H (1959) Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence-Moon-Bardet-Biedl syndrome: a clinical, endocrinological and genetic examination based on a large pedigree. Acta Psychiatr Neurol Scand Suppl 129, 1-35
25 Rahmouni K, Fath MA, Seo S et al (2008) Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest 118, 1458-1467   DOI
26 Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K and Sheffield VC (2009) Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet 18, 1323-1331   DOI
27 Berbari NF, Pasek RC, Malarkey EB et al (2013) Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice. Proc Natl Acad Sci U S A 110, 7796-7801   DOI
28 Collin GB, Marshall JD, Ikeda A et al (2002) Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet 31, 74-78
29 Hearn T, Renforth GL, Spalluto C et al (2002) Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet 31, 79-83
30 Hearn T, Spalluto C, Phillips VJ et al (2005) Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Diabetes 54, 1581-1587   DOI
31 Collin GB, Marshall JD, King BL et al (2012) The Alstrom syndrome protein, ALMS1, interacts with alpha-actinin and components of the endosome recycling pathway. PLoS One 7, e37925   DOI
32 Mukhopadhyay S and Jackson PK (2013) Cilia, tubby mice, and obesity. Cilia 2, 1   DOI
33 Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L and Anderson KV (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83-87   DOI
34 Davenport JR, Watts AJ, Roper VC et al (2007) Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol 17, 1586-1594   DOI
35 Berbari NF, Lewis JS, Bishop GA, Askwith CC and Mykytyn K (2008) Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A 105, 4242-4246   DOI
36 Jacoby M, Cox JJ, Gayral S et al (2009) INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet 41, 1027-1031   DOI
37 Thomas S, Cantagrel V, Mariani L et al (2015) Identification of a novel ARL13B variant in a Joubert syndrome- affected patient with retinal impairment and obesity. Eur J Hum Genet 23, 621-627   DOI
38 Jenkins D, Seelow D, Jehee FS et al (2007) RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet 80, 1162-1170   DOI
39 Shalata A, Ramirez MC, Desnick RJ et al (2013) Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice. Am J Hum Genet 93, 1061-1071   DOI
40 Varela L and Horvath TL (2012) Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 13, 1079-1086   DOI
41 Boehlke C, Kotsis F, Patel V et al (2010) Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat Cell Biol 12, 1115-1122   DOI
42 Zimmerman K and Yoder BK (2015) SnapShot: Sensing and Signaling by Cilia. Cell 161, 692-692 e1   DOI
43 Eggenschwiler JT and Anderson KV (2007) Cilia and developmental signaling. Annu Rev Cell Dev Biol 23, 345-373   DOI
44 Collins SP, Reoma JL, Gamm DM and Uhler MD (2000) LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem J 345 Pt 3, 673-680   DOI
45 Zick Y (2005) Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci STKE 2005, pe4
46 Moon H, Song J, Shin JO et al (2014) Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling. Proc Natl Acad Sci U S A 111, 8541-8546   DOI
47 Wu D, Chapman JR, Wang L et al (2012) Intestinal cell kinase (ICK) promotes activation of mTOR complex 1 (mTORC1) through phosphorylation of Raptor Thr-908. J Biol Chem 287, 12510-12519   DOI
48 Farooqi IS and O’Rahilly S (2005) Monogenic obesity in humans. Annu Rev Med 56, 443-458   DOI
49 Kim JC, Badano JL, Sibold S et al (2004) The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 36, 462-470   DOI