Cancer cachexia is a wasting syndrome characterized by reduced food intake and lean and fat tissue loss. In mice, cancer cachexia involved marked reductions in host fat and lean mass (particularly skeletal muscle), which were balanced by tumor growth. Using 15N tracing, the tumor gets protein (nitrogen) from both food intake and host tissue breakdown. Total energy expenditure remained unchanged due to metabolic compensation among the tumor, brown adipose tissue (BAT), and other organs, a phenomenon also observed in people with cancer. The decrease in leptin caused by fat loss did not stimulate food intake or reduce energy expenditure. We show that S100 calcium-binding protein A8 and A9 (S100A8/A9) and complement 3 (C3) in the hypothalamus play a key role in the reduction of food intake and fat mass during cancer cachexia. The peripheral administration of S100A8/A9 inhibitors and the hypothalamic knockdown of C3 significantly increased food intake and partially rescued fat and lean tissue loss.