Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia

Brennan Olson; Xinxia Zhu; Mason A. Norgard; Peter R. Levasseur; John T. Butler; Abigail Buenafe; Kevin G. Burfeind; Katherine A. Michaelis; Katherine R. Pelz; Heike Mendez; Jared Edwards; Stephanie Krasnow; Aaron J. Grossberg; Daniel L. Marks

doi:10.1038/s41467-021-22361-3

Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia

Brennan Olson, Xinxia Zhu, Mason A. Norgard, Peter R. Levasseur, John T. Butler, Abigail Buenafe, Kevin G. Burfeind, Katherine A. Michaelis, Katherine R. Pelz, Heike Mendez, Jared Edwards, Stephanie Krasnow, Aaron J. Grossberg, Daniel L. Marks

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20 Scopus citations

Abstract

Lipocalin 2 (LCN2) was recently identified as an endogenous ligand of the type 4 melanocortin receptor (MC4R), a critical regulator of appetite. However, it remains unknown if this molecule influences appetite during cancer cachexia, a devastating clinical entity characterized by decreased nutrition and progressive wasting. We demonstrate that LCN2 is robustly upregulated in murine models of pancreatic cancer, its expression is associated with reduced food consumption, and Lcn2 deletion is protective from cachexia-anorexia. Consistent with LCN2’s proposed MC4R-dependent role in cancer-induced anorexia, pharmacologic MC4R antagonism mitigates cachexia-anorexia, while restoration of Lcn2 expression in the bone marrow is sufficient in restoring the anorexia feature of cachexia. Finally, we observe that LCN2 levels correlate with fat and lean mass wasting and is associated with increased mortality in patients with pancreatic cancer. Taken together, these findings implicate LCN2 as a pathologic mediator of appetite suppression during pancreatic cancer cachexia.

Original language	English (US)
Article number	2057
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22361-3
State	Published - Dec 1 2021

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-021-22361-3

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title = "Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia",

abstract = "Lipocalin 2 (LCN2) was recently identified as an endogenous ligand of the type 4 melanocortin receptor (MC4R), a critical regulator of appetite. However, it remains unknown if this molecule influences appetite during cancer cachexia, a devastating clinical entity characterized by decreased nutrition and progressive wasting. We demonstrate that LCN2 is robustly upregulated in murine models of pancreatic cancer, its expression is associated with reduced food consumption, and Lcn2 deletion is protective from cachexia-anorexia. Consistent with LCN2{\textquoteright}s proposed MC4R-dependent role in cancer-induced anorexia, pharmacologic MC4R antagonism mitigates cachexia-anorexia, while restoration of Lcn2 expression in the bone marrow is sufficient in restoring the anorexia feature of cachexia. Finally, we observe that LCN2 levels correlate with fat and lean mass wasting and is associated with increased mortality in patients with pancreatic cancer. Taken together, these findings implicate LCN2 as a pathologic mediator of appetite suppression during pancreatic cancer cachexia.",

author = "Brennan Olson and Xinxia Zhu and Norgard, {Mason A.} and Levasseur, {Peter R.} and Butler, {John T.} and Abigail Buenafe and Burfeind, {Kevin G.} and Michaelis, {Katherine A.} and Pelz, {Katherine R.} and Heike Mendez and Jared Edwards and Stephanie Krasnow and Grossberg, {Aaron J.} and Marks, {Daniel L.}",

note = "Funding Information: We thank Drs Elizabeth Jaffee (KPC), David Tuveson (FC1242, FC1199, and FC1245), and Robert Vonderheide (4662) for graciously providing the syngeneic pancreatic cancer cell lines used for our studies. The graphical abstract and Fig. 4a were made using BioRender (BioRender.com). Finally, we thank Ashley J Olson, PA-C for technical assistance with the ICV AgRP study. This work was supported by NIH R01CA217989 (Marks), the Brenden-Colson Center for Pancreatic Care at OHSU (Marks), NIH K08CA245188 (Grossberg), and NIH F30CA254033 (Olson). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-22361-3",

language = "English (US)",

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AU - Olson, Brennan

AU - Zhu, Xinxia

AU - Norgard, Mason A.

AU - Levasseur, Peter R.

AU - Butler, John T.

AU - Buenafe, Abigail

AU - Burfeind, Kevin G.

AU - Michaelis, Katherine A.

AU - Pelz, Katherine R.

AU - Mendez, Heike

AU - Edwards, Jared

AU - Krasnow, Stephanie

AU - Grossberg, Aaron J.

AU - Marks, Daniel L.

N1 - Funding Information: We thank Drs Elizabeth Jaffee (KPC), David Tuveson (FC1242, FC1199, and FC1245), and Robert Vonderheide (4662) for graciously providing the syngeneic pancreatic cancer cell lines used for our studies. The graphical abstract and Fig. 4a were made using BioRender (BioRender.com). Finally, we thank Ashley J Olson, PA-C for technical assistance with the ICV AgRP study. This work was supported by NIH R01CA217989 (Marks), the Brenden-Colson Center for Pancreatic Care at OHSU (Marks), NIH K08CA245188 (Grossberg), and NIH F30CA254033 (Olson). Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Lipocalin 2 (LCN2) was recently identified as an endogenous ligand of the type 4 melanocortin receptor (MC4R), a critical regulator of appetite. However, it remains unknown if this molecule influences appetite during cancer cachexia, a devastating clinical entity characterized by decreased nutrition and progressive wasting. We demonstrate that LCN2 is robustly upregulated in murine models of pancreatic cancer, its expression is associated with reduced food consumption, and Lcn2 deletion is protective from cachexia-anorexia. Consistent with LCN2’s proposed MC4R-dependent role in cancer-induced anorexia, pharmacologic MC4R antagonism mitigates cachexia-anorexia, while restoration of Lcn2 expression in the bone marrow is sufficient in restoring the anorexia feature of cachexia. Finally, we observe that LCN2 levels correlate with fat and lean mass wasting and is associated with increased mortality in patients with pancreatic cancer. Taken together, these findings implicate LCN2 as a pathologic mediator of appetite suppression during pancreatic cancer cachexia.

AB - Lipocalin 2 (LCN2) was recently identified as an endogenous ligand of the type 4 melanocortin receptor (MC4R), a critical regulator of appetite. However, it remains unknown if this molecule influences appetite during cancer cachexia, a devastating clinical entity characterized by decreased nutrition and progressive wasting. We demonstrate that LCN2 is robustly upregulated in murine models of pancreatic cancer, its expression is associated with reduced food consumption, and Lcn2 deletion is protective from cachexia-anorexia. Consistent with LCN2’s proposed MC4R-dependent role in cancer-induced anorexia, pharmacologic MC4R antagonism mitigates cachexia-anorexia, while restoration of Lcn2 expression in the bone marrow is sufficient in restoring the anorexia feature of cachexia. Finally, we observe that LCN2 levels correlate with fat and lean mass wasting and is associated with increased mortality in patients with pancreatic cancer. Taken together, these findings implicate LCN2 as a pathologic mediator of appetite suppression during pancreatic cancer cachexia.

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ER -

Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia

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