PT - JOURNAL ARTICLE AU - Yang, Qiqi AU - Yan, Chuan AU - Wang, Xu AU - Gong, Zhiyuan TI - Leptin induces muscle wasting in a zebrafish <em>kras</em>-driven hepatocellular carcinoma (HCC) model AID - 10.1242/dmm.038240 DP - 2019 Feb 01 TA - Disease Models &amp; Mechanisms PG - dmm038240 VI - 12 IP - 2 4099 - http://dmm.biologists.org/content/12/2/dmm038240.short 4100 - http://dmm.biologists.org/content/12/2/dmm038240.full SO - Dis Models Mech2019 Feb 01; 12 AB - 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 krasG12V, 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.