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

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 inciden...

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Published inNature communications Vol. 16; no. 1; pp. 5608 - 18
Main Authors Tyagi, Abhishek, Wu, Shih-Ying, Kim, Jee-Won, Deshpande, Ravindra Pramod, Wu, Kerui, Smith, Eleanor C., Banna, Giuseppe L., Watabe, Kounosuke
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.07.2025
Nature Publishing Group
Nature Portfolio
Subjects
13/1
13/106
13/31
14/5
14/63
38/109
38/88
42/41
631/67/1612/1350
631/67/1857
631/67/2327
631/67/322
64/60
82/51
Aged
Animals
Biomarkers
Body Mass Index
Body size
Brain
Brain cancer
Brain Neoplasms - metabolism
Brain Neoplasms - secondary
Brain tumors
Calories
Cell growth
Cell Line, Tumor
Female
Ghrelin
Ghrelin - blood
Ghrelin - metabolism
Growth hormones
Humanities and Social Sciences
Humans
Immunohistochemistry
Lung cancer
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Male
Medical prognosis
Melanoma
Metastases
Metastasis
Mice
Middle Aged
Molecular modelling
Mortality
multidisciplinary
Neurons - metabolism
Neuropeptide Y
Neuropeptide Y - genetics
Neuropeptide Y - metabolism
Obesity
Obesity - complications
Obesity - metabolism
Paradoxes
Physiology
Receptors, Ghrelin - metabolism
Receptors, Neuropeptide Y - metabolism
Risk factors
Science
Science (multidisciplinary)
Secretion
Signal Transduction
Tumor cells
Tumors
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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. Low body mass index (BMI) is associated with increased brain metastasis risk in lung cancer patients. Here, the authors report that low-BMI increases neuronal secretion of neuropeptide Y (NPY), thereby activating the NPY receptor on lung tumor cells, leading to tumor metabolic reprogramming and brain metastasis.
AbstractList 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.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.
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.
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.
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. Low body mass index (BMI) is associated with increased brain metastasis risk in lung cancer patients. Here, the authors report that low-BMI increases neuronal secretion of neuropeptide Y (NPY), thereby activating the NPY receptor on lung tumor cells, leading to tumor metabolic reprogramming and brain metastasis.
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.Low body mass index (BMI) is associated with increased brain metastasis risk in lung cancer patients. Here, the authors report that low-BMI increases neuronal secretion of neuropeptide Y (NPY), thereby activating the NPY receptor on lung tumor cells, leading to tumor metabolic reprogramming and brain metastasis.
ArticleNumber 5608
Author Watabe, Kounosuke
Kim, Jee-Won
Wu, Kerui
Banna, Giuseppe L.
Wu, Shih-Ying
Smith, Eleanor C.
Tyagi, Abhishek
Deshpande, Ravindra Pramod
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Snippet 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...
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...
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Animals
Biomarkers
Body Mass Index
Body size
Brain
Brain cancer
Brain Neoplasms - metabolism
Brain Neoplasms - secondary
Brain tumors
Calories
Cell growth
Cell Line, Tumor
Female
Ghrelin
Ghrelin - blood
Ghrelin - metabolism
Growth hormones
Humanities and Social Sciences
Humans
Immunohistochemistry
Lung cancer
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Male
Medical prognosis
Melanoma
Metastases
Metastasis
Mice
Middle Aged
Molecular modelling
Mortality
multidisciplinary
Neurons - metabolism
Neuropeptide Y
Neuropeptide Y - genetics
Neuropeptide Y - metabolism
Obesity
Obesity - complications
Obesity - metabolism
Paradoxes
Physiology
Receptors, Ghrelin - metabolism
Receptors, Neuropeptide Y - metabolism
Risk factors
Science
Science (multidisciplinary)
Secretion
Signal Transduction
Tumor cells
Tumors
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Title Ghrelin-induced neuronal NPY promotes brain metastasis in lung cancer patients with low BMI
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