Diabetes and Metabolism Journal

Korean Diabetes Association (대한당뇨병학회)
권호 표지
DOI QR코드

DOI QR Code

Primary Cilia as a Signaling Platform for Control of Energy Metabolism

  • Song, Do Kyeong (Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Choi, Jong Han (Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Min-Seon (Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2018.01.25
  • Accepted : 2018.02.05
  • Published : 2018.04.18
⟨ Previous Next ⟩

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 $Alstr\ddot{o}m$ 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.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea

References

  1. Bhurosy T, Jeewon R. Overweight and obesity epidemic in developing countries: a problem with diet, physical activity, or socioeconomic status? Scientific World Journal 2014;2014:964236.
  2. Hruby A, Hu FB. The epidemiology of obesity: a big picture. Pharmacoeconomics 2015;33:673-89. https://doi.org/10.1007/s40273-014-0243-x
  3. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997;27:325-51. https://doi.org/10.1023/A:1025635913927
  4. Oh EC, Vasanth S, Katsanis N. Metabolic regulation and energy homeostasis through the primary Cilium. Cell Metab 2015; 21:21-31. https://doi.org/10.1016/j.cmet.2014.11.019
  5. Kebede MA, Attie AD. Insights into obesity and diabetes at the intersection of mouse and human genetics. Trends Endocrinol Metab 2014;25:493-501. https://doi.org/10.1016/j.tem.2014.06.006
  6. Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. J Hered 1950;41:317-8. https://doi.org/10.1093/oxfordjournals.jhered.a106073
  7. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263-71. https://doi.org/10.1016/0092-8674(95)90151-5
  8. Bloodgood RA. From central to rudimentary to primary: the history of an underappreciated organelle whose time has come. The primary cilium. Methods Cell Biol 2009;94:3-52.
  9. Berbari NF, O'Connor AK, Haycraft CJ, Yoder BK. The primary cilium as a complex signaling center. Curr Biol 2009;19:R526-35. https://doi.org/10.1016/j.cub.2009.05.025
  10. Hildebrandt F, Benzing T, Katsanis N. Ciliopathies. N Engl J Med 2011;364:1533-43. https://doi.org/10.1056/NEJMra1010172
  11. Louvi A, Grove EA. Cilia in the CNS: the quiet organelle claims center stage. Neuron 2011;69:1046-60. https://doi.org/10.1016/j.neuron.2011.03.002
  12. Christensen ST, Pedersen LB, Schneider L, Satir P. Sensory cilia and integration of signal transduction in human health and disease. Traffic 2007;8:97-109. https://doi.org/10.1111/j.1600-0854.2006.00516.x
  13. Hsiao YC, Tuz K, Ferland RJ. Trafficking in and to the primary cilium. Cilia 2012;1:4. https://doi.org/10.1186/2046-2530-1-4
  14. Cole DG, Diener DR, Himelblau AL, Beech PL, Fuster JC, Rosenbaum JL. Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J Cell Biol 1998;141:993-1008. https://doi.org/10.1083/jcb.141.4.993
  15. Pazour GJ, Wilkerson CG, Witman GB. A dynein light chain is essential for the retrograde particle movement of intraflagellar transport (IFT). J Cell Biol 1998;141:979-92. https://doi.org/10.1083/jcb.141.4.979
  16. Pazour GJ, Dickert BL, Vucica Y, Seeley ES, Rosenbaum JL, Witman GB, Cole DG. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol 2000;151:709-18. https://doi.org/10.1083/jcb.151.3.709
  17. Cortellino S, Wang C, Wang B, Bassi MR, Caretti E, Champeval D, Calmont A, Jarnik M, Burch J, Zaret KS, Larue L, Bellacosa A. Defective ciliogenesis, embryonic lethality and severe impairment of the sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4. Dev Biol 2009;325:225-37. https://doi.org/10.1016/j.ydbio.2008.10.020
  18. Takeda S, Yonekawa Y, Tanaka Y, Okada Y, Nonaka S, Hirokawa N. Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A-/- mice analysis. J Cell Biol 1999;145: 825-36. https://doi.org/10.1083/jcb.145.4.825
  19. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell 2008;15:801-12. https://doi.org/10.1016/j.devcel.2008.11.010
  20. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev 2008;22:2454-72. https://doi.org/10.1101/gad.1693608
  21. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993;75:1417-30. https://doi.org/10.1016/0092-8674(93)90627-3
  22. Krauss S, Concordet JP, Ingham PW. A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 1993;75:1431-44. https://doi.org/10.1016/0092-8674(93)90628-4
  23. Roelink H, Augsburger A, Heemskerk J, Korzh V, Norlin S, Ruiz i Altaba A, Tanabe Y, Placzek M, Edlund T, Jessell TM, Dodd J. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 1994;76:761-75. https://doi.org/10.1016/0092-8674(94)90514-2
  24. Kim J, Kato M, Beachy PA. Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus. Proc Natl Acad Sci U S A 2009;106:21666-71. https://doi.org/10.1073/pnas.0912180106
  25. Brennan D, Chen X, Cheng L, Mahoney M, Riobo NA. Noncanonical Hedgehog signaling. Vitam Horm 2012;88:55-72.
  26. Teperino R, Aberger F, Esterbauer H, Riobo N, Pospisilik JA. Canonical and non-canonical Hedgehog signalling and the control of metabolism. Semin Cell Dev Biol 2014;33:81-92. https://doi.org/10.1016/j.semcdb.2014.05.007
  27. Benzler J, Andrews ZB, Pracht C, Stohr S, Shepherd PR, Grattan DR, Tups A. Hypothalamic WNT signalling is impaired during obesity and reinstated by leptin treatment in male mice. Endocrinology 2013;154:4737-45. https://doi.org/10.1210/en.2013-1746
  28. Nusse R, Varmus H. Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J 2012;31: 2670-84. https://doi.org/10.1038/emboj.2012.146
  29. Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res 2010;106:1798-806. https://doi.org/10.1161/CIRCRESAHA.110.219840
  30. Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 1996;86:391-9. https://doi.org/10.1016/S0092-8674(00)80112-9
  31. Helfer G, Tups A. Hypothalamic Wnt signalling and its role in energy balance regulation. J Neuroendocrinol 2016;28:12368.
  32. Aznar N, Billaud M. Primary cilia bend LKB1 and mTOR to their will. Dev Cell 2010;19:792-4. https://doi.org/10.1016/j.devcel.2010.11.016
  33. Ravindran S, Kuruvilla V, Wilbur K, Munusamy S. Nephroprotective effects of metformin in diabetic nephropathy. J Cell Physiol 2017;232:731-42. https://doi.org/10.1002/jcp.25598
  34. Pampliega O, Cuervo AM. Autophagy and primary cilia: dual interplay. Curr Opin Cell Biol 2016;39:1-7. https://doi.org/10.1016/j.ceb.2016.01.008
  35. Tang Z, Lin MG, Stowe TR, Chen S, Zhu M, Stearns T, Franco B, Zhong Q. Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. Nature 2013;502:254-7. https://doi.org/10.1038/nature12606
  36. Pampliega O, Orhon I, Patel B, Sridhar S, Diaz-Carretero A, Beau I, Codogno P, Satir BH, Satir P, Cuervo AM. Functional interaction between autophagy and ciliogenesis. Nature 2013; 502:194-200. https://doi.org/10.1038/nature12639
  37. Jin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, Bazan JF, Nachury MV. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 2010;141:1208-19. https://doi.org/10.1016/j.cell.2010.05.015
  38. Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 2006;7:125-48. https://doi.org/10.1146/annurev.genom.7.080505.115610
  39. Jacobsson JA, Schioth HB, Fredriksson R. The impact of intronic single nucleotide polymorphisms and ethnic diversity for studies on the obesity gene FTO. Obes Rev 2012;13:1096-109. https://doi.org/10.1111/j.1467-789X.2012.01025.x
  40. Stratigopoulos G, Martin Carli JF, O’Day DR, Wang L, Leduc CA, Lanzano P, Chung WK, Rosenbaum M, Egli D, Doherty DA, Leibel RL. Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice. Cell Metab 2014;19:767-79. https://doi.org/10.1016/j.cmet.2014.04.009
  41. Millan MJ, Millan MH, Reid LD, Herz A. The role of the mediobasal arcuate hypothalamus in relation to opioid systems in the control of ingestive behaviour in the rat. Brain Res 1986; 381:29-42. https://doi.org/10.1016/0006-8993(86)90686-4
  42. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature 2006;443:289-95. https://doi.org/10.1038/nature05026
  43. Kang GM, Han YM, Ko HW, Kim J, Oh BC, Kwon I, Kim MS. Leptin elongates hypothalamic neuronal cilia via transcriptional regulation and actin destabilization. J Biol Chem 2015;290:18146-55. https://doi.org/10.1074/jbc.M115.639468
  44. Davenport JR, Watts AJ, Roper VC, Croyle MJ, van Groen T, Wyss JM, Nagy TR, Kesterson RA, Yoder BK. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol 2007;17:1586-94. https://doi.org/10.1016/j.cub.2007.08.034
  45. Han YM, Kang GM, Byun K, Ko HW, Kim J, Shin MS, Kim HK, Gil SY, Yu JH, Lee B, Kim MS. Leptin-promoted cilia assembly is critical for normal energy balance. J Clin Invest 2014; 124:2193-7. https://doi.org/10.1172/JCI69395
  46. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404:661-71. https://doi.org/10.1038/35007534
  47. Rahmouni K, Fath MA, Seo S, Thedens DR, Berry CJ, Weiss R, Nishimura DY, Sheffield VC. Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest 2008;118:1458-67. https://doi.org/10.1172/JCI32357
  48. Berbari NF, Pasek RC, Malarkey EB, Yazdi SM, McNair AD, Lewis WR, Nagy TR, Kesterson RA, Yoder BK. Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice. Proc Natl Acad Sci U S A 2013;110:7796-801. https://doi.org/10.1073/pnas.1210192110
  49. Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet 2009;18:1323-31. https://doi.org/10.1093/hmg/ddp031
  50. Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A 2008;105:4242-6. https://doi.org/10.1073/pnas.0711027105
  51. Seeley RJ, Woods SC. Monitoring of stored and available fuel by the CNS: implications for obesity. Nat Rev Neurosci 2003;4: 901-9. https://doi.org/10.1038/nrn1245
  52. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7. https://doi.org/10.1126/science.284.5411.143
  53. Marion V, Stoetzel C, Schlicht D, Messaddeq N, Koch M, Flori E, Danse JM, Mandel JL, Dollfus H. Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc Natl Acad Sci U S A 2009;106:1820-5. https://doi.org/10.1073/pnas.0812518106
  54. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA. Inhibition of adipogenesis by Wnt signaling. Science 2000;289:950-3. https://doi.org/10.1126/science.289.5481.950
  55. Wright WS, Longo KA, Dolinsky VW, Gerin I, Kang S, Bennett CN, Chiang SH, Prestwich TC, Gress C, Burant CF, Susulic VS, MacDougald OA. Wnt10b inhibits obesity in ob/ob and agouti mice. Diabetes 2007;56:295-303. https://doi.org/10.2337/db06-1339
  56. Suh JM, Gao X, McKay J, McKay R, Salo Z, Graff JM. Hedgehog signaling plays a conserved role in inhibiting fat formation. Cell Metab 2006;3:25-34. https://doi.org/10.1016/j.cmet.2005.11.012
  57. Pospisilik JA, Schramek D, Schnidar H, Cronin SJ, Nehme NT, Zhang X, Knauf C, Cani PD, Aumayr K, Todoric J, Bayer M, Haschemi A, Puviindran V, Tar K, Orthofer M, Neely GG, Dietzl G, Manoukian A, Funovics M, Prager G, Wagner O, Ferrandon D, Aberger F, Hui CC, Esterbauer H, Penninger JM. Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate. Cell 2010;140:148-60. https://doi.org/10.1016/j.cell.2009.12.027
  58. Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Connor T, Jaeger C, Kammerer B, Winter L, Wiche G, Dalgaard K, Selvaraj M, Gaster M, Lee-Young RS, Febbraio MA, Knauf C, Cani PD, Aberger F, Penninger JM, Pospisilik JA, Esterbauer H. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 2012;151:414-26. https://doi.org/10.1016/j.cell.2012.09.021
  59. Ogden SK, Fei DL, Schilling NS, Ahmed YF, Hwa J, Robbins DJ. G protein Galphai functions immediately downstream of smoothened in Hedgehog signalling. Nature 2008;456:967-70. https://doi.org/10.1038/nature07459
  60. Polizio AH, Chinchilla P, Chen X, Manning DR, Riobo NA. Sonic Hedgehog activates the GTPases Rac1 and RhoA in a Gli-independent manner through coupling of smoothened to Gi proteins. Sci Signal 2011;4:pt7.

Cited by

  1. Neuronal and astrocytic primary cilia in the mature brain vol.137, pp.None, 2018, https://doi.org/10.1016/j.phrs.2018.10.002
  2. O-GlcNAcylation Regulates Primary Ciliary Length by Promoting Microtubule Disassembly vol.12, pp.None, 2018, https://doi.org/10.1016/j.isci.2019.01.031
  3. Sonic hedgehog signaling instigates high-fat diet–induced insulin resistance by targeting PPARγ stability vol.294, pp.9, 2019, https://doi.org/10.1074/jbc.ra118.004411
  4. Cellular signalling by primary cilia in development, organ function and disease vol.15, pp.4, 2018, https://doi.org/10.1038/s41581-019-0116-9
  5. Interplay Between Primary Cilia and Autophagy and Its Controversial Roles in Cancer vol.27, pp.4, 2018, https://doi.org/10.4062/biomolther.2019.056
  6. High-resolution characterization of centriole distal appendage morphology and dynamics by correlative STORM and electron microscopy vol.10, pp.1, 2019, https://doi.org/10.1038/s41467-018-08216-4
  7. Evidences of a Direct Relationship between Cellular Fuel Supply and Ciliogenesis Regulated by Hypoxic VDAC1-ΔC vol.12, pp.11, 2018, https://doi.org/10.3390/cancers12113484
  8. Hypothalamic primary cilium: A hub for metabolic homeostasis vol.53, pp.7, 2021, https://doi.org/10.1038/s12276-021-00644-5