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

Area of Science:

• Endocrinology
• Oncology
• Metabolism

Background:

• Cancer-related anorexia-cachexia syndrome (CACS) involves significant weight loss and anorexia.
• Ghrelin is known to play a protective role in CACS, with elevated levels and administration showing beneficial effects.
• The role of liver-expressed antimicrobial peptide-2 (LEAP2), an endogenous ghrelin receptor antagonist, in CACS remains unexplored.

Purpose of the Study:

• To investigate the role of LEAP2 in cancer-related anorexia-cachexia syndrome (CACS).
• To determine the impact of ghrelin and LEAP2 manipulation on CACS phenotypes in preclinical models.
• To explore the association between the LEAP2/ghrelin ratio and weight changes in cancer patients with CACS.

Main Methods:

• Utilized Lewis lung carcinoma (LLC) and RM-9 prostate cancer mouse models of CACS.
• Generated ghrelin-deleted and LEAP2-deleted mouse models to assess their roles in CACS.
• Measured tumor-free body weight, fat mass, food intake, soleus muscle weight, and grip strength.
• Analyzed plasma LEAP2 and ghrelin levels in mouse models and a cohort of 55 cancer patients.

Main Results:

• Plasma LEAP2 levels and the LEAP2/ghrelin ratio were reduced in CACS mouse models.
• Ghrelin deletion exacerbated CACS, leading to greater weight and fat loss, reduced food intake, and decreased muscle mass and strength.
• LEAP2 deletion ameliorated CACS, reducing weight and fat loss and increasing food intake.
• In cancer patients, a lower plasma LEAP2/total ghrelin ratio correlated negatively with preceding 6-month weight change.

Conclusions:

• Ghrelin deletion worsens CACS, while LEAP2 deletion alleviates CACS in preclinical models.
• The findings suggest that a lower plasma LEAP2/ghrelin ratio is associated with worsened CACS.
• LEAP2 emerges as a potential therapeutic target or biomarker for managing CACS.