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The cilium: a cellular antenna with an influence on obesity risk

  • Edwin C. M. Mariman (a1), Roel G. Vink (a1), Nadia J. T. Roumans (a1), Freek G. Bouwman (a1), Constance T. R. M. Stumpel (a2) (a3), Erik E. J. G. Aller (a1), Marleen A. van Baak (a1) and Ping Wang (a2)...


Primary cilia are organelles that are present on many different cell types, either transiently or permanently. They play a crucial role in receiving signals from the environment and passing these signals to other parts of the cell. In that way, they are involved in diverse processes such as adipocyte differentiation and olfactory sensation. Mutations in genes coding for ciliary proteins often have pleiotropic effects and lead to clinical conditions, ciliopathies, with multiple symptoms. In this study, we reviewed observations from ciliopathies with obesity as one of the symptoms. It shows that variation in cilia-related genes is itself not a major cause of obesity in the population but may be a part of the multifactorial aetiology of this complex condition. Both common polymorphisms and rare deleterious variants may contribute to the obesity risk. Genotype–phenotype relationships have been noticed. Among the ciliary genes, obesity differs with regard to severity and age of onset, which may relate to the influence of each gene on the balance between pro- and anti-adipogenic processes. Analysis of the function and location of the proteins encoded by these ciliary genes suggests that obesity is more linked to activities at the basal area of the cilium, including initiation of the intraflagellar transport, but less to the intraflagellar transport itself. Regarding the role of cilia, three possible mechanistic processes underlying obesity are described: adipogenesis, neuronal food intake regulation and food odour perception.

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Corresponding author

* Corresponding author: E. C. M. Mariman, email


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1. Benzing, T & Schermer, B (2011) Transition zone proteins and cilia dynamics. Nat Genet 43, 723724.
2. 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, 776784.
3. Reiter, JF, Blacque, OE & 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, 608618.
4. Sang, L, Miller, JJ, Corbit, KC, et al. (2011) Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145, 513528.
5. Satir, P, Pedersen, LB & Christensen, ST (2010) The primary cilium at a glance. J Cell Sci 123, 499503.
6. Szymanska, K & Johnson, CA (2012) The transition zone: an essential functional compartment of cilia. Cilia 1, 10.
7. Valente, EM, Rosti, RO, Gibbs, E, et al. (2014) Primary cilia in neurodevelopmental disorders. Nat Rev Neurol 10, 2736.
8. Garcia-Gonzalo, FR & Reiter, JF (2012) Scoring a backstage pass: mechanisms of ciliogenesis and ciliary access. J Cell Biol 197, 697709.
9. Boekhoff, I, Tareilus, E, Strotmann, J, et al. (1990) Rapid activation of alternative second messenger pathways in olfactory cilia from rats by different odorants. EMBO J 9, 24532458.
10. Corbit, KC, Shyer, AE, Dowdle, WE, et al. (2008) Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat Cell Biol 10, 7076.
11. Goetz, SC & Anderson, KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11, 331344.
12. Rohatgi, R, Milenkovic, L & Scott, MP (2007) Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372376.
13. Schneider, L, Clement, CA, Teilmann, SC, et al. (2005) PDGFRalphaalpha signaling is regulated through the primary cilium in fibroblasts. Curr Biol 15, 18611866.
14. Baker, K & Beales, PL (2009) Making sense of cilia in disease: the human ciliopathies. Am J Med Genet C Semin Med Genet 151C, 281295.
15. Leitch, CC, Zaghloul, NA, Davis, EE, et al. (2008) Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet 40, 443448.
16. Forsythe, E & Beales, PL (2003) Bardet-Biedl Syndrome. In GeneReviews(R), pp. 19932016 [RA Pagon, MP Adam, HH Ardinger, SE Wallace, A Amemiya, LJH Bean, TD Bird, CR Dolan, CT Fong, RJH Smith and K Stephens, editors]. Seattle, WA: University of Washington.
17. Hampshire, DJ, Ayub, M, Springell, K, et al. (2006) MORM syndrome (mental retardation, truncal obesity, retinal dystrophy and micropenis), a new autosomal recessive disorder, links to 9q34. Eur J Hum Genet 14, 543548.
18. 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, 10271031.
19. 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, 10611071.
20. Marshall, JD, Maffei, P, Collin, GB, et al. (2011) Alstrom syndrome: genetics and clinical overview. Curr Genomics 12, 225235.
21. 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, 621627.
22. Hopp, K, Heyer, CM, Hommerding, CJ, et al. (2011) B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis. Hum Mol Genet 20, 25242534.
23. Harville, HM, Held, S, Diaz-Font, A, et al. (2010) Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping. J Med Genet 47, 262267.
24. Kulaga, HM, Leitch, CC, Eichers, ER, et al. (2004) Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nat Genet 36, 994998.
25. M’Hamdi, O, Redin, C, Stoetzel, C, et al. (2014) Clinical and genetic characterization of Bardet-Biedl syndrome in Tunisia: defining a strategy for molecular diagnosis. Clin Genet 85, 172177.
26. Bee, YM, Chawla, M & Zhao, Y (2015) Whole exome sequencing identifies a novel and a recurrent mutation in Bbs2 gene in a family with Bardet-Biedl syndrome. Biomed Res Int 2015, 524754.
27. Sheffield, VC, Carmi, R, Kwitek-Black, A, et al. (1994) Identification of a Bardet-Biedl syndrome locus on chromosome 3 and evaluation of an efficient approach to homozygosity mapping. Hum Mol Genet 3, 13311335.
28. Iannaccone, A, Mykytyn, K, Persico, AM, et al. (2005) Clinical evidence of decreased olfaction in Bardet-Biedl syndrome caused by a deletion in the BBS4 gene. Am J Med Genet A 132A, 343346.
29. Hjortshoj, TD, Gronskov, K, Philp, AR, et al. (2008) Novel mutations in BBS5 highlight the importance of this gene in non-Caucasian Bardet-Biedl syndrome patients. Am J Med Genet A 146A, 517520.
30. Slavotinek, AM, Stone, EM, Mykytyn, K, et al. (2000) Mutations in MKKS cause Bardet-Biedl syndrome. Nat Genet 26, 1516.
31. Nishimura, DY, Swiderski, RE, Searby, CC, et al. (2005) Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am J Hum Genet 77, 10211033.
32. Lim, ET, Liu, YP, Chan, Y, et al. (2014) A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity. Am J Hum Genet 95, 509520.
33. Chiang, AP, Beck, JS, Yen, HJ, et al. (2006) Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci U S A 103, 62876292.
34. Saccone, V, Palmieri, M, Passamano, L, et al. (2008) Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H. Hum Mutat 29, 240247.
35. Xing, DJ, Zhang, HX, Huang, N, et al. (2014) Comprehensive molecular diagnosis of Bardet-Biedl syndrome by high-throughput targeted exome sequencing. PLOS ONE 9, e90599.
36. Logan, CV, Abdel-Hamed, Z & Johnson, CA (2011) Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Mol Neurobiol 43, 1226.
37. McEwen, DP, Koenekoop, RK, Khanna, H, et al. (2007) Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons. Proc Natl Acad Sci USA 104, 1591715922.
38. Sayer, JA, Otto, EA, O’Toole, JF, et al. (2006) The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 38, 674681.
39. Baala, L, Audollent, S, Martinovic, J, et al. (2007) Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. Am J Hum Genet 81, 170179.
40. Kim, SK, Shindo, A, Park, TJ, et al. (2010) Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science 329, 13371340.
41. Billingsley, G, Vincent, A, Deveault, C, et al. (2012) Mutational analysis of SDCCAG8 in Bardet-Biedl syndrome patients with renal involvement and absent polydactyly. Ophthalmic Genet 33, 150154.
42. Otto, EA, Hurd, TW, Airik, R, et al. (2010) Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet 42, 840850.
43. Marion, V, Stutzmann, F, Gerard, M, et al. (2012) Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet-Biedl syndrome with situs inversus and insertional polydactyly. J Med Genet 49, 317321.
44. Scheidecker, S, Etard, C, Pierce, NW, et al. (2014) Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J Med Genet 51, 132136.
45. Aldahmesh, MA, Li, Y, Alhashem, A, et al. (2014) IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome. Hum Mol Genet 23, 33073315.
46. Tallila, J, Jakkula, E, Peltonen, L, et al. (2008) Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am J Hum Genet 82, 13611367.
47. Gorden, NT, Arts, HH, Parisi, MA, et al. (2008) CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am J Hum Genet 83, 559571.
48. Bouhouche, A, Benomar, A, Bouslam, N, et al. (2006) Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia. J Med Genet 43, 441443.
49. Arts, HH, Bongers, EM, Mans, DA, et al. (2011) C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome. J Med Genet 48, 390395.
50. Tuysuz, B, Baris, S, Aksoy, F, et al. (2009) Clinical variability of asphyxiating thoracic dystrophy (Jeune) syndrome: evaluation and classification of 13 patients. Am J Med Genet A 149A, 17271733.
51. McIntyre, JC, Davis, EE, Joiner, A, et al. (2012) Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model. Nat Med 18, 14231428.
52. Walczak-Sztulpa, J, Eggenschwiler, J, Osborn, D, et al. (2010) Cranioectodermal dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am J Hum Genet 86, 949956.
53. Davis, EE, Zhang, Q, Liu, Q, et al. (2011) TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 43, 189196.
54. Huynh Cong, E, Bizet, AA, Boyer, O, et al. (2014) A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS. J Am Soc Nephrol 25, 24352443.
55. Schmidts, M, Frank, V, Eisenberger, T, et al. (2013) Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney disease. Hum Mutat 34, 714724.
56. Perrault, I, Saunier, S, Hanein, S, et al. (2012) Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. Am J Hum Genet 90, 864870.
57. Bredrup, C, Saunier, S, Oud, MM, et al. (2011) Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am J Hum Genet 89, 634643.
58. Bujakowska, KM, Zhang, Q, Siemiatkowska, AM, et al. (2015) Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome. Hum Mol Genet 24, 230242.
59. Lucas-Herald, AK, Kinning, E, Iida, A, et al. (2015) A case of functional growth hormone deficiency and early growth retardation in a child with IFT172 mutations. J Clin Endocrinol Metab 100, 12211224.
60. Cole, DG, Diener, DR, Himelblau, AL, et al. (1998) Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J Cell Biol 141, 9931008.
61. Travaglini, L, Brancati, F, Silhavy, J, et al. (2013) Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders. Eur J Hum Genet 21, 10741078.
62. Ala-Mello, S, Koskimies, O, Rapola, J, et al. (1999) Nephronophthisis in Finland: epidemiology and comparison of genetically classified subgroups. Eur J Hum Genet 7, 205211.
63. Parisi, MA, Bennett, CL, Eckert, ML, et al. (2004) The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 75, 8291.
64. Caridi, G, Murer, L, Bellantuono, R, et al. (1998) Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am J Kidney Dis 32, 10591062.
65. Schuermann, MJ, Otto, E, Becker, A, et al. (2002) Mapping of gene loci for nephronophthisis type 4 and Senior-Loken syndrome, to chromosome 1p36. Am J Hum Genet 70, 12401246.
66. Thomas, S, Wright, KJ, Le Corre, S, et al. (2014) A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum Mutat 35, 137146.
67. Delous, M, Baala, L, Salomon, R, et al. (2007) The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 39, 875881.
68. Doherty, D, Parisi, MA, Finn, LS, et al. (2010) Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J Med Genet 47, 821.
69. Arts, HH, Doherty, D, van Beersum, SE, et al. (2007) Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nat Genet 39, 882888.
70. Shaheen, R, Faqeih, E, Seidahmed, MZ, et al. (2011) A TCTN2 mutation defines a novel Meckel Gruber syndrome locus. Hum Mutat 32, 573578.
71. Smith, UM, Consugar, M, Tee, LJ, et al. (2006) The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet 38, 191196.
72. Romano, S, Boddaert, N, Desguerre, I, et al. (2006) Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study. Neuropediatrics 37, 4245.
73. Otto, EA, Tory, K, Attanasio, M, et al. (2009) Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11). J Med Genet 46, 663670.
74. Valente, EM, Logan, CV, Mougou-Zerelli, S, et al. (2010) Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 42, 619625.
75. Edvardson, S, Shaag, A, Zenvirt, S, et al. (2010) Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation. Am J Hum Genet 86, 9397.
76. Huang, L, Szymanska, K, Jensen, VL, et al. (2011) TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am J Hum Genet 89, 713730.
77. Kudryashova, E, Wu, J, Havton, LA, et al. (2009) Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component. Hum Mol Genet 18, 13531367.
78. Acs, P, Bauer, PO, Mayer, B, et al. (2015) A novel form of ciliopathy underlies hyperphagia and obesity in Ankrd26 knockout mice. Brain Struct Funct 220, 15111528.
79. Dong, C, Li, WD, Geller, F, et al. (2005) Possible genomic imprinting of three human obesity-related genetic loci. Am J Hum Genet 76, 427437.
80. Noben-Trauth, K, Naggert, JK, North, MA, et al. (1996) A candidate gene for the mouse mutation tubby. Nature 380, 534538.
81. Sun, X, Haley, J, Bulgakov, OV, et al. (2012) Tubby is required for trafficking G protein-coupled receptors to neuronal cilia. Cilia 1, 21.
82. 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, 12011213.
83. Jenkins, PM, McEwen, DP & Martens, JR (2009) Olfactory cilia: linking sensory cilia function and human disease. Chem Senses 34, 451464.
84. Williams, CL, McIntyre, JC, Norris, SR, et al. (2014) Direct evidence for BBSome-associated intraflagellar transport reveals distinct properties of native mammalian cilia. Nat Commun 5, 5813.
85. Jin, H & Nachury, MV (2009) The BBSome. Curr Biol 19, R472R473.
86. Seo, S, Baye, LM, Schulz, NP, et al. (2010) BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc Natl Acad Sci U S A 107, 14881493.
87. Zhang, Q, Yu, D, Seo, S, et al. (2012) Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the BBSome. J Biol Chem 287, 2062520635.
88. Loktev, AV, Zhang, Q, Beck, JS, et al. (2008) A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell 15, 854865.
89. Behal, RH, Miller, MS, Qin, H, et al. (2012) Subunit interactions and organization of the Chlamydomonas reinhardtii intraflagellar transport complex A proteins. J Biol Chem 287, 1168911703.
90. Rosenbaum, JL & Witman, GB (2002) Intraflagellar transport. Nat Rev Mol Cell Biol 3, 813825.
91. Davis, EE & Katsanis, N (2014) Dissecting intraflagellar transport, one molecule at a time. Dev Cell 31, 263264.
92. Eguether, T, San Agustin, JT, Keady, BT, et al. (2014) IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment. Dev Cell 31, 279290.
93. Liew, GM, Ye, F, Nager, AR, et al. (2014) The intraflagellar transport protein IFT27 promotes BBSome exit from cilia through the GTPase ARL6/BBS3. Dev Cell 31, 265278.
94. Nachury, MV, Seeley, ES & Jin, H (2010) Trafficking to the ciliary membrane: how to get across the periciliary diffusion barrier? Annu Rev Cell Dev Biol 26, 5987.
95. Wiens, CJ, Tong, Y, Esmail, MA, et al. (2010) Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. J Biol Chem 285, 1621816230.
96. Botilde, Y, Yoshiba, S, Shinohara, K, et al. (2013) Cluap1 localizes preferentially to the base and tip of cilia and is required for ciliogenesis in the mouse embryo. Dev Biol 381, 203212.
97. Lee, C, Wallingford, JB & Gross, JM (2014) Cluap1 is essential for ciliogenesis and photoreceptor maintenance in the vertebrate eye. Invest Ophthalmol Vis Sci 55, 45854592.
98. Gupta, GD, Coyaud, E, Goncalves, J, et al. (2015) A dynamic protein interaction landscape of the human centrosome-cilium interface. Cell 163, 14841499.
99. 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, 15811587.
100. Jagger, D, Collin, G, Kelly, J, et al. (2011) Alstrom syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity. Hum Mol Genet 20, 466481.
101. Leitch, CC, Lodh, S, Prieto-Echague, V, et al. (2014) Basal body proteins regulate Notch signaling through endosomal trafficking. J Cell Sci 127, 24072419.
102. Williams, CL, Li, C, Kida, K, et al. (2011) MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol 192, 10231041.
103. Gerhardt, C, Lier, JM, Burmuhl, S, et al. (2015) The transition zone protein Rpgrip1l regulates proteasomal activity at the primary cilium. J Cell Biol 210, 115133.
104. Stratigopoulos, G, Martin Carli, JF, O’Day, DR, et al. (2014) Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice. Cell Metab 19, 767779.
105. Heymsfield, SB, Avena, NM, Baier, L, et al. (2014) Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia. Obesity (Silver Spring) 22, Suppl. 1, S1S17.
106. Bielas, SL, Silhavy, JL, Brancati, F, et al. (2009) Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 41, 10321036.
107. Chavez, M, Ena, S, Van Sande, J, et al. (2015) Modulation of ciliary phosphoinositide content regulates trafficking and sonic hedgehog signaling output. Dev Cell 34, 338350.
108. Garcia-Gonzalo, FR, Phua, SC, Roberson, EC, et al. (2015) Phosphoinositides regulate ciliary protein trafficking to modulate hedgehog signaling. Dev Cell 34, 400409.
109. Park, J, Lee, N, Kavoussi, A, et al. (2015) Ciliary phosphoinositide regulates ciliary protein trafficking in drosophila. Cell Rep 13, 28082816.
110. Humbert, MC, Weihbrecht, K, Searby, CC, et al. (2012) ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proc Natl Acad Sci U S A 109, 1969119696.
111. Nordman, S, Abulaiti, A, Hilding, A, et al. (2008) Genetic variation of the adenylyl cyclase 3 (AC3) locus and its influence on type 2 diabetes and obesity susceptibility in Swedish men. Int J Obes (Lond) 32, 407412.
112. Wang, H, Wu, M, Zhu, W, et al. (2010) Evaluation of the association between the AC3 genetic polymorphisms and obesity in a Chinese Han population. PLoS ONE 5, e13851.
113. Wang, Z, Li, V, Chan, GC, et al. (2009) Adult type 3 adenylyl cyclase-deficient mice are obese. PLoS ONE 4, e6979.
114. Wong, ST, Trinh, K, Hacker, B, et al. (2000) Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Neuron 27, 487497.
115. Diaz-Font, A & Beales, PL (2008) How to shape cells and influence polarized protein trafficking. Dev Cell 15, 799800.
116. Xu, J, Li, H, Wang, B, et al. (2010) VHL inactivation induces HEF1 and aurora kinase A. J Am Soc Nephrol 21, 20412046.
117. Pugacheva, EN, Jablonski, SA, Hartman, TR, et al. (2007) HEF1-dependent aurora A activation induces disassembly of the primary cilium. Cell 129, 13511363.
118. Plotnikova, OV, Seo, S, Cottle, DL, et al. (2015) INPP5E interacts with AURKA, linking phosphoinositide signaling to primary cilium stability. J Cell Sci 128, 364372.
119. Yuan, X, Serra, RA & Yang, S (2015) Function and regulation of primary cilia and intraflagellar transport proteins in the skeleton. Ann N Y Acad Sci 1335, 7899.
120. Knorz, VJ, Spalluto, C, Lessard, M, et al. (2010) Centriolar association of ALMS1 and likely centrosomal functions of the ALMS motif-containing proteins C10orf90 and KIAA1731. Mol Biol Cell 21, 36173629.
121. Seixas, C, Choi, SY, Polgar, N, et al. (2016) Arl13b and the exocyst interact synergistically in ciliogenesis. Mol Biol Cell 27, 308320.
122. Cui, C, Chatterjee, B, Lozito, TP, et al. (2013) Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton. PLoS Biol 11, e1001720.
123. Seo, S, Zhang, Q, Bugge, K, et al. (2011) A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened. PLoS Genet 7, e1002358.
124. Halbritter, J, Bizet, AA, Schmidts, M, et al. (2013) Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. Am J Hum Genet 93, 915925.
125. Feuillan, PP, Ng, D, Han, JC, et al. (2011) Patients with Bardet-Biedl syndrome have hyperleptinemia suggestive of leptin resistance. J Clin Endocrinol Metab 96, E528E535.
126. Grace, C, Beales, P, Summerbell, C, et al. (2003) Energy metabolism in Bardet-Biedl syndrome. Int J Obes Relat Metab Disord 27, 13191324.
127. Cox, KF, Kerr, NC, Kedrov, M, et al. (2012) Phenotypic expression of Bardet-Biedl syndrome in patients homozygous for the common M390R mutation in the BBS1 gene. Vision Res 75, 7787.
128. Davis, RE, Swiderski, RE, Rahmouni, K, et al. (2007) A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. Proc Natl Acad Sci U S A 104, 1942219427.
129. Carmi, R, Elbedour, K, Stone, EM, et al. (1995) Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci. Am J Med Genet 59, 199203.
130. Benzinou, M, Walley, A, Lobbens, S, et al. (2006) Bardet-Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians. Diabetes 55, 28762882.
131. Andersen, KL, Echwald, SM, Larsen, LH, et al. (2005) Variation of the McKusick-Kaufman gene and studies of relationships with common forms of obesity. J Clin Endocrinol Metab 90, 225230.
132. Birk, RZ, Ermakov, S & Livshits, G (2013) Common FSNP variants of fourteen Bardet-Biedl syndrome genes and adult body mass. Obesity (Silver Spring) 21, 16841689.
133. Reed, DR, Ding, Y, Xu, W, et al. (1995) Human obesity does not segregate with the chromosomal regions of Prader-Willi, Bardet-Biedl, Cohen, Borjeson or Wilson-Turner syndromes. Int J Obes Relat Metab Disord 19, 599603.
134. Mariman, EC, Bouwman, FG, Aller, EE, et al. (2014) High frequency of rare variants with a moderate-to-high predicted biological effect in protocadherin genes of extremely obese. Genes Nutr 9, 399.
135. Mariman, EC, Szklarczyk, R, Bouwman, FG, et al. (2015) Olfactory receptor genes cooperate with protocadherin genes in human extreme obesity. Genes Nutr 10, 465.
136. Li, JB, Gerdes, JM, Haycraft, CJ, et al. (2004) Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117, 541552.
137. Rask-Andersen, M, Almen, MS & Schioth, HB (2015) Scrutinizing the FTO locus: compelling evidence for a complex, long-range regulatory context. Hum Genet 134, 11831193.
138. Tung, YC, Yeo, GS, O’Rahilly, S, et al. (2014) Obesity and FTO: changing focus at a complex locus. Cell Metab 20, 710718.
139. Chennen, K, Scerbo, MJ, Dollfus, H, et al. (2014) [Bardet-Biedl syndrome: cilia and obesity – from genes to integrative approaches]. Med Sci (Paris) 30, 10341039.
140. Guemez-Gamboa, A, Coufal, NG & Gleeson, JG (2014) Primary cilia in the developing and mature brain. Neuron 82, 511521.
141. Mok, CA, Heon, E & Zhen, M (2010) Ciliary dysfunction and obesity. Clin Genet 77, 1827.
142. Oh, EC, Vasanth, S & Katsanis, N (2015) Metabolic regulation and energy homeostasis through the primary Cilium. Cell Metab 21, 2131.
143. Sen Gupta, P, Prodromou, NV & Chapple, JP (2009) Can faulty antennae increase adiposity? The link between cilia proteins and obesity. J Endocrinol 203, 327336.
144. 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, 363377.
145. Huang-Doran, I & Semple, RK (2010) Knockdown of the Alstrom syndrome-associated gene Alms1 in 3T3-L1 preadipocytes impairs adipogenesis but has no effect on cell-autonomous insulin action. Int J Obes (Lond) 34, 15541558.
146. Zhu, D, Shi, S, Wang, H, et al. (2009) Growth arrest induces primary-cilium formation and sensitizes IGF-1-receptor signaling during differentiation induction of 3T3-L1 preadipocytes. J Cell Sci 122, 27602768.
147. Marion, V, Stoetzel, C, Schlicht, D, et al. (2009) Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc Natl Acad Sci U S A 106, 18201825.
148. Dalbay, MT, Thorpe, SD, Connelly, JT, et al. (2015) Adipogenic differentiation of hMSCs is mediated by recruitment of IGF-1r onto the primary cilium associated with cilia elongation. Stem Cells 33, 19521961.
149. Forcioli-Conti, N, Lacas-Gervais, S, Dani, C, et al. (2015) The primary cilium undergoes dynamic size modifications during adipocyte differentiation of human adipose stem cells. Biochem Biophys Res Commun 458, 117122.
150. North, BJ, Marshall, BL, Borra, MT, et al. (2003) The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 11, 437444.
151. Singla, V & Reiter, JF (2006) The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science 313, 629633.
152. Skurk, T, Alberti-Huber, C, Herder, C, et al. (2007) Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 92, 10231033.
153. Marshall, JD, Muller, J, Collin, GB, et al. (2015) Alstrom syndrome: mutation spectrum of ALMS1. Hum Mutat 36, 660668.
154. Berisha, SZ, Serre, D, Schauer, P, et al. (2011) Changes in whole blood gene expression in obese subjects with type 2 diabetes following bariatric surgery: a pilot study. PLoS ONE 6, e16729.
155. Vink, R, Roumans, NJ, Arkenbosch, LA, et al. (2016) The effect of rate of weight loss on long-term weight regain in adults with overweight and obesity. Obesity 24, 321327.
156. Rossmeislova, L, Malisova, L, Kracmerova, J, et al. (2013) Weight loss improves the adipogenic capacity of human preadipocytes and modulates their secretory profile. Diabetes 62, 19901995.
157. Han, YM, Kang, GM, Byun, K, et al. (2014) Leptin-promoted cilia assembly is critical for normal energy balance. J Clin Invest 124, 21932197.
158. Kang, GM, Han, YM, Ko, HW, et al. (2015) Leptin elongates hypothalamic neuronal cilia via transcriptional regulation and actin destabilization. J Biol Chem 290, 1814618155.
159. 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, 14581467.
160. 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, 15861594.
161. Seo, S, Guo, DF, Bugge, K, et al. (2009) Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet 18, 13231331.
162. 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, 77967801.
163. Loktev, AV & Jackson, PK (2013) Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. Cell Rep 5, 13161329.
164. Berbari, NF, Lewis, JS, Bishop, GA, et al. (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, 42424246.
165. Stepanow, S, Reichwald, K, Huse, K, et al. (2011) Allele-specific, age-dependent and BMI-associated DNA methylation of human MCHR1. PLoS ONE 6, e17711.
166. Heydet, D, Chen, LX, Larter, CZ, et al. (2013) A truncating mutation of Alms1 reduces the number of hypothalamic neuronal cilia in obese mice. Dev Neurobiol 73, 113.
167. Braun, JJ, Noblet, V, Durand, M, et al. (2014) Olfaction evaluation and correlation with brain atrophy in Bardet-Biedl syndrome. Clin Genet 86, 521529.
168. Tadenev, AL, Kulaga, HM, May-Simera, HL, et al. (2011) Loss of Bardet-Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting. Proc Natl Acad Sci U S A 108, 1032010325.
169. Nishimura, DY, Fath, M, Mullins, RF, et al. (2004) Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proc Natl Acad Sci U S A 101, 1658816593.
170. Ross, AJ, May-Simera, H, Eichers, ER, et al. (2005) Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet 37, 11351140.
171. Lee, MS, Hwang, KS, Oh, HW, et al. (2015) IFT46 plays an essential role in cilia development. Dev Biol 400, 248257.
172. Lehman, JM, Michaud, EJ, Schoeb, TR, et al. (2008) The Oak Ridge Polycystic Kidney mouse: modeling ciliopathies of mice and men. Dev Dyn 237, 19601971.
173. Lee, J, Tucker, RM, Tan, SY, et al. (2015) Nutritional implications of taste and smell dysfunction. In Handbook of Olfaction and Gustation, pp. 829864 [RL Doty, editor]. Hoboken, NJ: John Wiley and Sons Inc.
174. Aschenbrenner, K, Hummel, C, Teszmer, K, et al. (2008) The influence of olfactory loss on dietary behaviors. Laryngoscope 118, 135144.
175. Duffy, VB, Backstrand, JR & Ferris, AM (1995) Olfactory dysfunction and related nutritional risk in free-living, elderly women. J Am Diet Assoc 95, 879884; quiz 885–876.
176. Dwyer, ND, Adler, CE, Crump, JG, et al. (2001) Polarized dendritic transport and the AP-1 mu1 clathrin adaptor UNC-101 localize odorant receptors to olfactory cilia. Neuron 31, 277287.
177. Stephan, AB, Tobochnik, S, Dibattista, M, et al. (2012) The Na(+)/Ca(2+) exchanger NCKX4 governs termination and adaptation of the mammalian olfactory response. Nat Neurosci 15, 131137.
178. Antunes, G, Sebastiao, AM & Simoes de Souza, FM (2014) Mechanisms of regulation of olfactory transduction and adaptation in the olfactory cilium. PLOS ONE 9, e105531.
179. Choquette, AC, Bouchard, L, Drapeau, V, et al. (2012) Association between olfactory receptor genes, eating behavior traits and adiposity: results from the Quebec Family Study. Physiol Behav 105, 772776.
180. Jarick, I, Vogel, CI, Scherag, S, et al. (2011) Novel common copy number variation for early onset extreme obesity on chromosome 11q11 identified by a genome-wide analysis. Hum Mol Genet 20, 840852.
181. Tucker, K, Overton, JM & Fadool, DA (2012) Diet-induced obesity resistance of Kv1.3-/- mice is olfactory bulb dependent. J Neuroendocrinol 24, 10871095.
182. Hasegawa, S, Hirabayashi, T, Kondo, T, et al. (2012) Constitutively expressed Protocadherin-alpha regulates the coalescence and elimination of homotypic olfactory axons through its cytoplasmic region. Front Mol Neurosci 5, 97.
183. Lushchak, OV, Carlsson, MA & Nassel, DR (2015) Food odors trigger an endocrine response that affects food ingestion and metabolism. Cell Mol Life Sci 72, 31433155.
184. Palouzier-Paulignan, B, Lacroix, MC, Aime, P, et al. (2012) Olfaction under metabolic influences. Chem Senses 37, 769797.
185. Stafford, LD & Whittle, A (2015) Obese individuals have higher preference and sensitivity to odor of chocolate. Chem Senses 40, 279284.
186. Patel, BP, Aschenbrenner, K, Shamah, D, et al. (2015) Greater perceived ability to form vivid mental images in individuals with high compared to low BMI. Appetite 91, 185189.
187. Seo, S, Mullins, RF, Dumitrescu, AV, et al. (2013) Subretinal gene therapy of mice with Bardet-Biedl syndrome type 1. Invest Ophthalmol Vis Sci 54, 61186132.
188. Alinejad, B, Shafiee-Nick, R, Sadeghian, H, et al. (2015) Metabolic effects of newly synthesized phosphodiesterase-3 inhibitor 6-[4-(4-methylpiperidin-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one on rat adipocytes. Daru 23, 19.
189. Sahu, M, Anamthathmakula, P & Sahu, A (2015) Phosphodiesterase-3B-cAMP pathway of leptin signalling in the hypothalamus is impaired during the development of diet-induced obesity in FVB/N mice. J Neuroendocrinol 27, 293302.
190. Rahimi, R, Ghiasi, S, Azimi, H, et al. (2010) A review of the herbal phosphodiesterase inhibitors; future perspective of new drugs. Cytokine 49, 123129.
191. Pendleton, M, Brown, S, Thomas, CM, et al. (2013) Potential toxicity of caffeine when used as a dietary supplement for weight loss. J Diet Suppl 10, 15.


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The cilium: a cellular antenna with an influence on obesity risk

  • Edwin C. M. Mariman (a1), Roel G. Vink (a1), Nadia J. T. Roumans (a1), Freek G. Bouwman (a1), Constance T. R. M. Stumpel (a2) (a3), Erik E. J. G. Aller (a1), Marleen A. van Baak (a1) and Ping Wang (a2)...


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