TY - JOUR
T1 - Lipocalin 2 mediates appetite suppression during pancreatic cancer cachexia
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 M.
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
Y1 - 2021/12
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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U2 - 10.1038/s41467-021-22361-3
DO - 10.1038/s41467-021-22361-3
M3 - Article
C2 - 33824339
AN - SCOPUS:85103982464
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2057
ER -