The LEAP2 Response to Cancer-Related Anorexia-Cachexia Syndrome in Male Mice and Patients

Salil Varshney, Kripa Shankar, Haiming L Kerr, Lindsey J Anderson, Deepali Gupta, Nathan P Metzger, Omprakash Singh, Sean B Ogden, Subhojit Paul, Francisco Piñon, Sherri Osborne-Lawrence, Corine P Richard, Connor Lawrence, Bharath K Mani, Jose M Garcia, Jeffrey M Zigman
Endocrinology, Volume 165, Issue 11, November 2024, bqae132
https://doi.org/10.1210/endocr/bqae132

Abstract

The hormone ghrelin serves a protective role in cancer-related anorexia-cachexia syndrome (CACS) — a condition in which plasma levels of ghrelin rise, its administration lessens CACS severity, and experimentally reduced signaling by its receptor (GHSR) worsens fat loss and anorexia and accelerates death. Yet actions for the related hormone liver-expressed antimicrobial peptide-2 (LEAP2), which is an endogenous GHSR antagonist, are unexplored in CACS. Here, we found that plasma LEAP2 and LEAP2/ghrelin ratio were lower in Lewis lung carcinoma (LLC) and RM-9 prostate cancer CACS mouse models. Ghrelin deletion exaggerated losses of tumor-free body weight and fat mass, reduced food intake, reduced soleus muscle weight, and/or lowered grip strength in LLC or RM-9 tumor-bearing mice. LEAP2 deletion lessened reductions in tumor-free body weight and fat mass and increased food intake in LLC or RM-9 tumor-bearing mice. In a 55-subject cohort of patients with CACS or weight-stable cancer, the plasma LEAP2/total ghrelin ratio was negatively correlated with 6-month weight change preceding blood collection. These data demonstrate that ghrelin deletion exacerbates CACS in the LLC and RM-9 tumor-bearing mouse models while contrastingly, LEAP2 deletion reduces measures of CACS in these tumor-bearing mouse models. Further, they suggest that lower plasma LEAP2/ghrelin ratio protects against worsened CACS.

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