Cancer-associated cachexia (CAC) is a common syndrome in cancer patients and is characterized by loss of body weight accompanied by the atrophy of fat and skeletal muscle. Metabolic changes are a critical factor in CAC; however, the mechanisms through which tumors inhibit adipogenesis and promote lipolysis are poorly understood. To clarify these mechanisms, we investigated adipogenesis-limiting factors released by tumors in a cell culture system. We identified proliferin-1 (PLF-1), a member of the growth hormone/prolactin gene family, as a key factor secreted from certain tumors that inhibited preadipocyte maturation and promoted the lipolysis of mature adipocytes. Importantly, mice transplanted with PLF-1-depleted tumor cells were protected from fat loss due to CAC. These data show that tumor-secreted PLF-1 plays an essential role in impaired adipogenesis and accelerated lipolysis and is a potential therapeutic target against CAC.