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Nature Medicine 13, 1333–1340 (1 November 2007) | doi:10.1038/nm1677

Tumor-induced anorexia and weight loss are mediated by the TGF-|[beta]| superfamily cytokine MIC-1

Heiko Johnen , Shu Lin , Tamara Kuffner , David A Brown , Vicky Wang-Wei Tsai , Asne R Bauskin , Liyun Wu , Greg Pankhurst , Lele Jiang , Simon Junankar , Mark Hunter , W Douglas Fairlie , Nicola J Lee , Ronaldo F Enriquez , Paul A Baldock , Eva Corey , Fred S Apple , MaryAnn M Murakami , En-Ju Lin , Chuansong Wang , Matthew J During , Amanda Sainsbury , Herbert Herzog & Samuel N Breit

Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-β receptor II, extracellular signal–regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.