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’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.

Neural Mechanisms of Cancer Cachexia

“…Utilizing pancreatic ductal adenocarcinoma (PDAC)-associated cancer cachexia models, we demonstrated a clear appetite-regulatory role of LCN2 during the progression of PDAC cachexia [98]. Genetic deletion of lcn2 improved feeding behaviors and mitigated fat and muscle wasting.…”

Obesity and Pancreatic Cancer: Insight into Mechanisms

“…LCN2 has been implicated in the pathogenesis of various pancreatic diseases, including PDAC, acute and chronic pancreatitis, and T2DM [127]. LCN2 is upregulated in PDAC mouse models, correlates to decreased food intake, and its absence protects from tumor cachexia, presumably via a type 4 melanocortin receptor-mediated mechanism [128]. Increased LCN2 expression has been found in human PanINs and PDAC [129][130][131].…”

Physiologic and molecular characterization of a novel murine model of metastatic head and neck cancer cachexia

“… 31 Several plausible explanations could explain the cardiac‐sparing in MLM3‐cachexia in female mice, including the role of improved nutrition in cardiac cachexia (as anorexia is absent in the MLM3 model), unique inflammatory cytokine profiles and signalling, involvement (or lack thereof) of the sympathetic nervous system on cardiac tissue, and specific tumour‐derived factors' influence on cardiac pathophysiology. 28 Finally, because we observed a lower degree and number of MLM3‐engrafted female mice experiencing metastatic lesions to the lung, it is possible that the metastatic cascade is critically important for the development of wasting in this model. Additionally, female mice may experience lessened tissue catabolism due to their smaller tumour growth compared with their male counterparts.…”

“…MLM5 mice displayed significantly increased blood glucose levels at the time of sacrifice compared to MLM3‐engrafted mice, potentially owing to their improved caloric intake ( Figure S1C ). 28 MLM5‐engrafted mice displayed an intermediate hepatic inflammatory gene profile between sham and MLM5‐engrafted mice, as indicated by Il‐1β , Il‐6 , and Orm1 gene expression, although none of these were significantly altered compared with the MLM3 group alone ( Figure S1D ). Interestingly, MLM5‐engrafted mice displayed significantly larger spleens compared with the MLM3 group ( Figure S1E ).…”

“…We and others described CNS‐based mechanisms of cachexia in which systemic inflammatory signals are received and amplified by the hypothalamus, resulting in aberrant activity of weight‐modulating and activity‐modulating neurons. 4 , 28 , 64 , 65 , 66 , 67 To this end, we broadly characterized the inflammatory status in the mediobasal hypothalamus of MLM3‐engrafted mice. We observed an elevation of the inflammatory cytokine Il‐1b in cachectic mice after MLM3 implantation, along with an increase in hypothalamic glial cells (astrocytes and microglia).…”