Tumor necrosis factor-α (TNF-α) is known to participate in the wastage syndrome that accompanies cancer and severe infectious diseases. More recently, a role for TNF-α in the pathogenesis of type 2 diabetes mellitus and obesity has been shown. Much of the regulatory action exerted by TNF-α upon the control of energy stores depends on its action on the hypothalamus. In this study, we show that TNF-α activates canonical pro-inflammatory signal transduction pathways in the hypothalamus of rats. These signaling events lead to the transcriptional activation of an early responsive gene and to the induction of expression of cytokines and a cytokine responsive protein such as interleukin-1β, interleukin-6, interleukin-10 and suppressor of cytokine signalling-3, respectively. In addition, TNF-α induces the expression of neurotransmitters involved in the control of feeding and thermogenesis. Thus, TNF-α may act directly in the hypothalamus inducing a pro-inflammatory response and the modulation of expression of neurotransmitters involved in energy homeostasis.