The pathogenesis of cancer anorexia is multifactorial and is associated with disturbances of the central physiological mechanisms controlling food intake. However the neurochemical mechanisms responsible for cancer induced-anorexia are unclear. Here, we show that chronic infusion of 5-amino-4imidazolecarboxamide-riboside (AICAR) into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-D-glucose (2DG) promotes hypothalamic AMPK activation, increases food intake and prolongs the survival of anorexic tumor bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals, markedly reduced the hypothalamic production of inducible nitric oxide synthase (iNOS), interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-) and modulated the expression of POMC, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and i.c.v. treatment with biguanide anti diabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia.