Primary cilia and obesity: mechanistic insights and therapeutic perspectives

Öz

Primary cilia are sensory organelles that play a critical role in detecting and processing extracellular signals and have recently emerged as central regulators of energy homeostasis. Despite the rapid global rise in obesity prevalence, the molecular mechanisms governing energy intake and expenditure remain incompletely understood. In this context, primary cilia serve as a unique platform that spatially organizes key metabolic signaling pathways, including Hedgehog, Wnt/β-catenin, PDGF, and cAMP-dependent cascades. Disruption of ciliary integrity has been linked to metabolic phenotypes such as hyperphagia and reduced energy expenditure in hypothalamic neurons, abnormal differentiation and lipogenesis in adipocytes, and impaired glucose responsiveness in pancreatic β-cells. The severe obesity observed in ciliopathies such as Bardet–Biedl and Alström syndromes further underscores the essential role of ciliary function in maintaining metabolic health. At the molecular level, intraflagellar transport mechanisms, ciliary GPCR localization, and ADCY3-enriched cAMP microdomains shape the capacity of primary cilia to integrate metabolic signals. Perturbations in these processes exert multifaceted effects on energy balance across both central and peripheral tissues. Although cilia-targeted therapeutic approaches are theoretically promising, major translational challenges—including tissue specificity, long-term safety, and systemic effects—remain unresolved. This review summarizes the structural and functional properties of primary cilia, highlights their roles in metabolic regulation, and examines the molecular links between ciliary dysfunction and obesity. It also emphasizes the need for further mechanistic and translational studies to evaluate the feasibility of targeting primary cilia as a therapeutic strategy.

Anahtar Kelimeler

• Primary cilia
• obesity
• ciliopathies
• energy homeostasis
• hypothalamus

Primer siliyer ve obezite: mekanistik yaklaşımlar ve terapötik perspektifler

Öz

Primer siliyer (Primary cilia), hücre dışı sinyallerin algılanması ve işlenmesinde kritik rol oynayan duyusal organeller olup, son yıllarda enerji homeostazının düzenlenmesinde merkezi bir bileşen olarak öne çıkmıştır. Küresel obezite insidansındaki hızlı artışa rağmen, enerji alımı ve harcamasını belirleyen moleküler mekanizmalar tam olarak çözülememiştir. Bu bağlamda primer siliyer; Hedgehog, Wnt/β-katenin, PDGF ve cAMP-bağımlı yollar gibi metabolik açıdan belirleyici sinyal ağlarının organize edildiği özgün bir platform sunar. Siliyer bütünlüğün bozulması, hipotalamik nöronlarda hiperfaji ve azalmış enerji harcaması; adipositlerde anormal farklılaşma ve lipogenez; pankreatik β-hücrelerde ise glukoz yanıtında zayıflama gibi metabolik fenotiplerle ilişkilendirilmiştir. Bardet–Biedl ve Alström sendromu gibi siliyopati hastalıklarında görülen ağır obezite, siliyer fonksiyonların metabolik sağlık için vazgeçilmez olduğunu doğrulayan önemli klinik örneklerdir. Moleküler düzeyde, intraflagellar transport mekanizmaları, siliyer G proteinine bağlı reseptör (GPCR) dağılımı ve adenilat siklaz 3 (ADCY3) aracılı siklik adenozin monofosfat (cAMP) mikrobölgeleri, siliye’nin metabolik sinyalleri entegre etme kapasitesini şekillendirmektedir. Bu süreçlerdeki bozulmalar hem merkezi hem de periferik dokularda enerji dengesi üzerinde çok yönlü etkiler oluşturur. Siliyer hedefli terapötik yaklaşımlar teorik olarak umut verici olsa da dokuya özgüllük, uzun dönem güvenlik ve sistemik etkiler açısından önemli translasyonel kısıtlamalar mevcuttur. Bu derleme, primer siliyerin yapısal ve fonksiyonel özelliklerini, metabolik düzenlemedeki rollerini ve siliyer disfonksiyonun obeziteyle ilişkili mekanizmalarını özetlemekte; ayrıca bu organelin terapötik hedef olarak değerlendirilmesi için daha fazla mekanistik ve translasyonel araştırmaya duyulan ihtiyacı vurgulamaktadır.

Anahtar Kelimeler

• Primer siliyer
• obezite
• silyopatiler
• enerji homeostazı
• hipotalamus

Kaynakça

1. Ahmed SK, Mohammed RA. Obesity: Prevalence, causes, consequences, management, preventive strategies and future research directions. Metabolism Open. 2025;27:100375.
2. Drozdz D, Alvarez-Pitti J, Wójcik M, et al. Obesity and Cardiometabolic Risk Factors: From Childhood to Adulthood. Nutrients. 2021;13(11):4176.
3. Lopez-Jimenez F, Almahmeed W, Bays H, et al. Obesity and cardiovascular disease: mechanistic insights and management strategies. A joint position paper by the World Heart Federation and World Obesity Federation. European Journal of Preventive Cardiology. 2022;29(17):2218-37.
4. Gogas Yavuz D, Akhtar O, Low K, et al. The Economic Impact of Obesity in Turkey: A Micro-Costing Analysis. Clinicoecon Outcomes Res. 2024;16:123-32.
5. Song DK, Choi JH, Kim MS. Primary Cilia as a Signaling Platform for Control of Energy Metabolism. Diabetes Metab J. 2018;42(2):117-27.
6. Marshall WF, Nonaka S. Cilia: Tuning in to the Cell's Antenna. Current Biology. 2006;16(15):R604-R14.
7. Oh EC, Vasanth S, Katsanis N. Metabolic regulation and energy homeostasis through the primary Cilium. Cell Metab. 2015;21(1):21-31.
8. Waters AM, Beales PL. Ciliopathies: an expanding disease spectrum. Pediatr Nephrol. 2011;26(7):1039-56.

9. Forsythe E, Beales PL. Bardet–Biedl syndrome. European Journal of Human Genetics. 2013;21(1):8-13.
10. Brewer KM, Brewer KK, Richardson NC, Berbari NF. Neuronal cilia in energy homeostasis. Front Cell Dev Biol. 2022;10:1082141.
11. Anvarian Z, Mykytyn K, Mukhopadhyay S, Pedersen LB, Christensen ST. Cellular signalling by primary cilia in development, organ function and disease. Nat Rev Nephrol. 2019;15(4):199-219.
12. Mill P, Christensen ST, Pedersen LB. Primary cilia as dynamic and diverse signalling hubs in development and disease. Nat Rev Genet. 2023;24(7):421-41.
13. Yuan X, Serra RA, Yang S. Function and regulation of primary cilia and intraflagellar transport proteins in the skeleton. Ann N Y Acad Sci. 2015;1335(1):78-99.
14. Webb S, Mukhopadhyay AG, Roberts AJ. Intraflagellar transport trains and motors: Insights from structure. Semin Cell Dev Biol. 2020;107:82-90.
15. Čajánek L, Smite S, Ivashchenko O, Huranova M. Cilia at the crossroad: convergence of regulatory mechanisms to govern cilia dynamics during cell signaling and the cell cycle. Cell Biosci. 2025;15(1):81.
16. Berbari NF, Pasek RC, Malarkey EB, et al. Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice. Proc Natl Acad Sci U S A. 2013;110(19):7796-801.
17. Han YM, Kang GM, Byun K, et al. Leptin-promoted cilia assembly is critical for normal energy balance. J Clin Invest. 2014;124(5):2193-7.
18. Wang Y, Bernard A, Comblain F, et al. Melanocortin 4 receptor signals at the neuronal primary cilium to control food intake and body weight. J Clin Invest. 2021;131(9).
19. Yavuz Y, Ozen DO, Erol ZY, Goren H, Yilmaz B. Effects of endocrine disruptors on the electrical activity of leptin receptor neurons in the dorsomedial hypothalamus and anxiety-like behavior in male mice. Environ Pollut. 2023;324:121366.
20. Vaisse C, Reiter JF, Berbari NF. Cilia and Obesity. Cold Spring Harb Perspect Biol. 2017;9(7).
21. Han YG, Alvarez-Buylla A. Role of primary cilia in brain development and cancer. Curr Opin Neurobiol. 2010;20(1):58-67.
22. Green JA, Mykytyn K. Neuronal ciliary signaling in homeostasis and disease. Cell Mol Life Sci. 2010;67(19):3287-97.
23. Davenport JR, Watts AJ, Roper VC, et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol. 2007;17(18):1586-94.
24. López M. Hypothalamic Leptin Resistance: From BBB to BBSome. PLoS Genet. 2016;12(5):e1005980.
25. Scamfer SR, Lee MD, Hilgendorf KI. Ciliary control of adipocyte progenitor cell fate regulates energy storage. Front Cell Dev Biol. 2022;10:1083372.
26. Hilgendorf KI. Primary Cilia Are Critical Regulators of White Adipose Tissue Expansion. Front Physiol. 2021;12:769367.
27. Rahmouni K, Fath MA, Seo S, et al. Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest. 2008;118(4):1458-67.
28. Volta F, Scerbo MJ, Seelig A, et al. Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing. Nature Communications. 2019;10(1):5686.
29. Gerdes JM, Christou-Savina S, Xiong Y, et al. Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents. Nat Commun. 2014;5:5308.
30. Kim J, Hsia EY, Brigui A, et al. The role of ciliary trafficking in Hedgehog receptor signaling. Sci Signal. 2015;8(379):ra55.
31. Sigafoos AN, Paradise BD, Fernandez-Zapico ME. Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease. Cancers (Basel). 2021;13(14).
32. Prestwich TC, Macdougald OA. Wnt/beta-catenin signaling in adipogenesis and metabolism. Curr Opin Cell Biol. 2007;19(6):612-7.
33. Xue C, Chu Q, Shi Q, et al. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduction and Targeted Therapy. 2025;10(1):106.
34. Wu Y, Zhou J, Yang Y. Peripheral and central control of obesity by primary cilia. Journal of Genetics and Genomics. 2023;50(5):295-304.
35. Xun Y, Jiang Y, Xu B, et al. GPR45 modulates Gα(s) at primary cilia of the paraventricular hypothalamus to control food intake. Science. 2025;388(6751):eadp3989.
36. Ruban A, Stoenchev K, Ashrafian H, Teare J. Current treatments for obesity. Clin Med (Lond). 2019;19(3):205-12.
37. Cong G, Zhu X, Chen XR, Chen H, Chong W. Mechanisms and therapeutic potential of the hedgehog signaling pathway in cancer. Cell Death Discovery. 2025;11(1):40.
38. Forsythe E, Beales PL. Bardet-Biedl syndrome. Eur J Hum Genet. 2013;21(1):8-13.
39. Forsythe E, Kenny J, Bacchelli C, Beales PL. Managing Bardet-Biedl Syndrome-Now and in the Future. Front Pediatr. 2018;6:23.
40. Tahani N, Maffei P, Dollfus H, et al. Consensus clinical management guidelines for Alström syndrome. Orphanet J Rare Dis. 2020;15(1):253.
41. Raguram A, Banskota S, Liu DR. Therapeutic in vivo delivery of gene editing agents. Cell. 2022;185(15):2806-27.
42. Seoane-Collazo P, Fernø J, Gonzalez F, et al. Hypothalamic-autonomic control of energy homeostasis. Endocrine. 2015;50(2):276-91.
43. Quarta C, Claret M, Zeltser LM, et al. POMC neuronal heterogeneity in energy balance and beyond: an integrated view. Nat Metab. 2021;3(3):299-308.
44. Kajimura S, Spiegelman BM, Seale P. Brown and Beige Fat: Physiological Roles beyond Heat Generation. Cell Metab. 2015;22(4):546-59.
45. Jacobs DT, Silva LM, Allard BA, et al. Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome. Dis Model Mech. 2016;9(7):789-98.
46. Wang L, Meece K, Williams DJ, et al. Differentiation of hypothalamic-like neurons from human pluripotent stem cells. J Clin Invest. 2015;125(2):796-808.
47. Zhao Z, Chen X, Dowbaj AM, et al. Organoids. Nature Reviews Methods Primers. 2022;2(1):94.