Ghrelin-induced brain NPY drives brain metastasis in lean lung cancer patients—the "obesity paradox" explained | Research

The takeaway

Low BMI lung cancer patients have higher brain metastasis due to elevated ghrelin → neuronal NPY production → NPY receptor activation on cancer cells promoting brain invasion, with high-fat diet and NPY receptor blockade reducing metastasis in mice.

Ghrelin-NPY drives brain metastasis
Elevated ghrelin in lean lung cancer patients stimulates neuronal NPY production that promotes cancer invasion into the brain—explaining the "obesity paradox" and identifying a drug target

What the researchers found

Low BMI → ↑ghrelin → ↑neuronal NPY → NPY receptor activation on cancer cells → ↑brain metastasis. HFD (↓ghrelin) → ↓brain metastasis. NPY receptor blockade → ↓brain metastasis. Clinical: ↑ghrelin/NPY + ↑brain mets in low-BMI lung cancer. "Obesity paradox" explained.

Why it matters

Brain metastasis is often fatal. Understanding that lean patients' elevated ghrelin/NPY drives brain invasion provides a targetable mechanism—NPY receptor antagonists could prevent brain metastasis.

How the study worked

Clinical data: BMI, ghrelin, NPY, brain metastasis in lung cancer patients. Mouse models: HFD, NPY receptor blockade. In vitro: NPY effects on cancer cell invasion.

What this study cannot tell us

Correlation between BMI and brain metastasis may have other explanations. Mouse HFD model is simplified. NPY receptor subtypes not differentiated. Clinical data observational.

How to read the evidence

Translational study with clinical + mouse + in vitro evidence. Strong mechanistic chain.

When this study was published

Published in 2025.

The bigger picture

This solves a major cancer paradox and identifies peptide hormones (ghrelin, NPY) as unexpected drivers of cancer metastasis. NPY receptor antagonists could become anti-metastatic drugs.

Questions still open

Could NPY receptor antagonists prevent brain metastasis in lean cancer patients?
Does nutritional support (increasing BMI) reduce brain metastasis risk?
Are other cancer types also affected by the ghrelin-NPY axis?

Common questions

Why do thinner cancer patients get more brain metastasis?

This study found that lean lung cancer patients have higher levels of the hunger hormone ghrelin, which triggers brain cells to produce NPY (neuropeptide Y). NPY then helps cancer cells invade the brain. Essentially, being lean elevates hormones that inadvertently create a welcoming environment for cancer in the brain.

Could blocking NPY prevent brain cancer spread?

In mice, blocking NPY receptors reduced brain metastasis from lung cancer. A high-fat diet (which lowers ghrelin and therefore NPY) also reduced it. This suggests NPY receptor-blocking drugs could become a new strategy for preventing brain metastasis, especially in lean cancer patients.

Read the original research

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

Nature communications, 16(1), 5608

View on PubMed ↗Publisher’s paper ↗

Citation

Tyagi, Abhishek; Wu, Shih-Ying; Kim, Jee-Won; Deshpande, Ravindra Pramod; Wu, Kerui; Smith, Eleanor C; Banna, Giuseppe L; Watabe, Kounosuke. (2025). Ghrelin-induced neuronal NPY promotes brain metastasis in lung cancer patients with low BMI.. Nature communications, 16(1), 5608. https://doi.org/10.1038/s41467-025-60730-4