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 M. Krasnow, Aaron J. Grossberg and Daniel L. Marks ()
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Brennan Olson: Papé Family Pediatric Research Institute, Oregon Health & Science University
Xinxia Zhu: Papé Family Pediatric Research Institute, Oregon Health & Science University
Mason A. Norgard: Papé Family Pediatric Research Institute, Oregon Health & Science University
Peter R. Levasseur: Papé Family Pediatric Research Institute, Oregon Health & Science University
John T. Butler: Papé Family Pediatric Research Institute, Oregon Health & Science University
Abigail Buenafe: Papé Family Pediatric Research Institute, Oregon Health & Science University
Kevin G. Burfeind: Papé Family Pediatric Research Institute, Oregon Health & Science University
Katherine A. Michaelis: Papé Family Pediatric Research Institute, Oregon Health & Science University
Katherine R. Pelz: Oregon Health and & Science University
Heike Mendez: Oregon Health and & Science University
Jared Edwards: Papé Family Pediatric Research Institute, Oregon Health & Science University
Stephanie M. Krasnow: Papé Family Pediatric Research Institute, Oregon Health & Science University
Aaron J. Grossberg: Oregon Health and & Science University
Daniel L. Marks: Papé Family Pediatric Research Institute, Oregon Health & Science University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22361-3

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