Leptin induces muscle wasting in a zebrafish kras-driven hepatocellular carcinoma (HCC) model

Cancer cachexia affects up to 80% of patients with advanced solid cancer and leads to excessive muscle wasting. Here, using an inducible zebrafish hepatocellular carcinoma (HCC) model driven by oncogenic kras(G12V), we observed a progressive muscle-wasting phenotype in adult zebrafish, characterized by significant loss of body weight and muscle fibers. By differential feeding, we observed that overfeeding caused fatty liver, accelerated carcinogenesis and muscle wasting. Interestingly, leptin, an obesity hormone, was upregulated in oncogenic hepatocytes and overfeeding groups. We also found that leptin expression progressively increased during human liver disease progression. By using leptin receptor (lepr)-knockout fish, we found that tumor fish in the lepr mutant background had a higher survival rate and significantly lower muscle-wasting level after tumor induction than the tumor fish in the wild-type background. Chemical inhibitors targeting leptin signaling also alleviated the muscle-wasting phenotype, indicating that leptin signaling may be a new therapeutic target for cancer patients with muscle wasting.