IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60730-4.html
   My bibliography  Save this article

Ghrelin-induced neuronal NPY promotes brain metastasis in lung cancer patients with low BMI

Author

Listed:
  • Abhishek Tyagi

    (Wake Forest University School of Medicine)

  • Shih-Ying Wu

    (Wake Forest University School of Medicine)

  • Jee-Won Kim

    (Wake Forest University School of Medicine)

  • Ravindra Pramod Deshpande

    (Wake Forest University School of Medicine)

  • Kerui Wu

    (Joint School of Nanoscience & Nanoengineering)

  • Eleanor C. Smith

    (Wake Forest University School of Medicine)

  • Giuseppe L. Banna

    (University of Portsmouth)

  • Kounosuke Watabe

    (Wake Forest University School of Medicine)

Abstract

Obesity is a known risk factor for many cancers, yet recent studies reveal a paradoxical association between low body mass index (BMI) and increased brain metastasis in lung cancer—referred to as the “obesity paradox,” with unclear molecular mechanism(s). Here, we show a significantly higher incidence of brain metastasis in low-BMI lung cancer patients compared to those with high-BMI or other cancer brain metastasis in a pan-analysis of 7628 patients. Mechanistically, low BMI activates ghrelin-GHSR signaling, increasing neuronal neuropeptide Y (NPY) secretion, which promotes tumor metabolic reprogramming via NPY-Y5R, facilitating brain colonization. Elevated plasma ghrelin levels in cancer-free low-BMI subjects suggest its potential as a prognostic biomarker for predicting brain metastasis. Notably, targeting NPY-Y5R or reversing low BMI effectively suppresses brain metastasis, supporting its pro-metastatic role. These findings provide a strong rationale for developing targeted interventions to treat or prevent brain metastasis in lung cancer patients with low BMI.

Suggested Citation

  • Abhishek Tyagi & Shih-Ying Wu & Jee-Won Kim & Ravindra Pramod Deshpande & Kerui Wu & Eleanor C. Smith & Giuseppe L. Banna & Kounosuke Watabe, 2025. "Ghrelin-induced neuronal NPY promotes brain metastasis in lung cancer patients with low BMI," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60730-4
    DOI: 10.1038/s41467-025-60730-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60730-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60730-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Qi Zhang & Rober Abdo & Cristiana Iosef & Tomonori Kaneko & Matthew Cecchini & Victor K. Han & Shawn Shun-Cheng Li, 2022. "The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Masayasu Kojima & Hiroshi Hosoda & Yukari Date & Masamitsu Nakazato & Hisayuki Matsuo & Kenji Kangawa, 1999. "Ghrelin is a growth-hormone-releasing acylated peptide from stomach," Nature, Nature, vol. 402(6762), pages 656-660, December.
    3. Masamitsu Nakazato & Noboru Murakami & Yukari Date & Masayasu Kojima & Hisayuki Matsuo & Kenji Kangawa & Shigeru Matsukura, 2001. "A role for ghrelin in the central regulation of feeding," Nature, Nature, vol. 409(6817), pages 194-198, January.
    4. Congyi Lu & Akanksha Mahajan & Sung-Hyeok Hong & Susana Galli & Shiya Zhu & Jason U. Tilan & Nouran Abualsaud & Mina Adnani & Stacey Chung & Nada Elmansy & Jasmine Rodgers & Olga Rodriguez & Christoph, 2022. "Publisher Correction: Hypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    5. Congyi Lu & Akanksha Mahajan & Sung-Hyeok Hong & Susana Galli & Shiya Zhu & Jason U. Tilan & Nouran Abualsaud & Mina Adnani & Stacey Chung & Nada Elmansy & Jasmine Rodgers & Olga Rodriguez & Christoph, 2022. "Hypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. repec:plo:pone00:0035708 is not listed on IDEAS
    2. Sarah M. Mohr & Rafael Dai Pra & Maryann P. Platt & Viktor V. Feketa & Marya Shanabrough & Luis Varela & Ashley Kristant & Haoran Cao & Dana K. Merriman & Tamas L. Horvath & Sviatoslav N. Bagriantsev , 2024. "Hypothalamic hormone deficiency enables physiological anorexia in ground squirrels during hibernation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. K. Tanaka & T. Takizawa & O. Oki & K. Fukawa & T. Ito & M. Miyabe & H. Mannen & Y. Kurosawa & K. Hirose, 2015. "Allele frequency for c.335 A>C polymorphisms in porcine ghrelin/obestatin prepropeptide gene and association analysis with performance traits in various pig breeds," Czech Journal of Animal Science, Czech Academy of Agricultural Sciences, vol. 60(9), pages 411-416.
    4. Qian Wang, 2017. "The Ghrelin/GHS-R1a Pathway is Involved in the Mechanism of the CTA-regulated Neuronal Loop," International Journal of Sciences, Office ijSciences, vol. 6(01), pages 64-72, January.
    5. A. Lotfi & H. Aghdam-Shahryar & J. Ghiasi-Ghalehkandi & H. Kaiya & N. Maheri-Sis, 2011. "Effect of in ovo ghrelin administration on subsequent serum insulin and glucose levels in newly-hatched chicks," Czech Journal of Animal Science, Czech Academy of Agricultural Sciences, vol. 56(8), pages 377-380.
    6. Anna Skakodub & Henry Walch & Kathryn R. Tringale & Jordan Eichholz & Brandon S. Imber & Harish N. Vasudevan & Bob T. Li & Nelson S. Moss & Kenny Kwok Hei Yu & Boris A. Mueller & Simon Powell & Pedram, 2023. "Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Kuanhan Feng & Xinru Zhang & Jiale Li & Mingzhi Han & Jinghuang Wang & Fucai Chen & Zhiwen Yi & Liuqing Di & Ruoning Wang, 2025. "Neoantigens combined with in situ cancer vaccination induce personalized immunity and reshape the tumor microenvironment," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    8. Gerrit Vortmeier & Stephanie H DeLuca & Sylvia Els-Heindl & Constance Chollet & Holger A Scheidt & Annette G Beck-Sickinger & Jens Meiler & Daniel Huster, 2015. "Integrating Solid-State NMR and Computational Modeling to Investigate the Structure and Dynamics of Membrane-Associated Ghrelin," PLOS ONE, Public Library of Science, vol. 10(3), pages 1-28, March.
    9. Nazan Yurtcu & Canan Soyer Caliskan & Huri Guvey & Samettin Celik & Safak Hatirnaz & Andrea Tinelli, 2022. "Predictive and Diagnostic Value of Serum Adipokines in Pregnant Women with Intrahepatic Cholestasis," IJERPH, MDPI, vol. 19(4), pages 1-13, February.
    10. Mahalaqua Nazli Khatib & Anuraj Shankar & Richard Kirubakaran & Kingsley Agho & Padam Simkhada & Shilpa Gaidhane & Deepak Saxena & Unnikrishnan B & Dilip Gode & Abhay Gaidhane & Syed Quazi Zahiruddin, 2015. "Effect of Ghrelin on Mortality and Cardiovascular Outcomes in Experimental Rat and Mice Models of Heart Failure: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 10(5), pages 1-21, May.
    11. Gökçen Demiray & Serkan Degirmenciogl & Erhan Ugurlu & Aydin Demiray & Arzu Yaren & Hakan Akc & Gamze Gököz Dogu, 2018. "Relationship between serum ghrelin levels, weight loss and quality of life in patients with advanced non-small cell lung cancer," International Journal of Cell Science & Molecular Biology, Juniper Publishers Inc., vol. 4(5), pages 99-104, July.
    12. Chengdi Wang & Jingwei Li & Jingyao Chen & Zhoufeng Wang & Guonian Zhu & Lujia Song & Jiayang Wu & Changshu Li & Rong Qiu & Xuelan Chen & Li Zhang & Weimin Li, 2025. "Multi-omics analyses reveal biological and clinical insights in recurrent stage I non-small cell lung cancer," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    13. Michelle L Johnson & M Jill Saffrey & Victoria J Taylor, 2016. "Plasma Ghrelin Concentrations Were Altered with Oestrous Cycle Stage and Increasing Age in Reproductively Competent Wistar Females," PLOS ONE, Public Library of Science, vol. 11(11), pages 1-12, November.
    14. repec:plo:pone00:0065422 is not listed on IDEAS
    15. Amy J. Pearl & Xavier J. Maddern & Paulo Pinares-Garcia & Lauren T. Ursich & Roberta G. Anversa & Arnav Shesham & Robyn M. Brown & Felicia M. Reed & William J. Giardino & Andrew J. Lawrence & Leigh C., 2025. "Midbrain ghrelin receptor signalling regulates binge drinking in a sex specific manner," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    16. Meng Zhang & Liu Yang & Xue Mi & Gonghui Hu & Yingchang Lu & Chen Wang & Jie Yang & Xiaomin Sun & Minglu Niu & Xianchao Li & Sihan Wang & Jingsai Zhang & Hanbing Yu & Yuyang Wang & Ming Yu & Nan Li & , 2025. "GHS-R1a signaling drives anxiety-related behavior by shaping excitability of ventromedial hypothalamic neurons," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    17. Mohammed Saeed Al-Ayed & Khaled Sadeq Al-Shaibari & Dhafer Alshehri & Mohammed Jamaan Alzahrani & Iman Nasser & Hamdan Saad Alaamri & Wed Ahmad Alaseeri & Ahmed A. Mahfouz & Saeed Ali Alsareii & Ahmed, 2020. "Serum Ghrelin Levels in Saudi Obese Asthmatic School-Children—Correlation with Interleukin-4, Interleukin-5, and Interleukin-21," IJERPH, MDPI, vol. 17(5), pages 1-11, March.
    18. Luca Franchini & Joseph J. Porter & John D. Lueck & Cesare Orlandi, 2025. "GzESTY as an optimized cell-based assay for initial steps in GPCR deorphanization," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    19. Amany M Basuny & Moustafa A AboelAnin & Eman A Hamed, 2020. "Structure and Physiological Functions of Ghrelin," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 31(2), pages 24085-24092, October.
    20. Enrica Bianchi & Kim Boekelheide & Mark Sigman & Susan J Hall & Kathleen Hwang, 2017. "Ghrelin modulates testicular damage in a cryptorchid mouse model," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-17, May.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60730-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.