TNFα is an important mediator of catabolism in cachexia. Most of its effects have been characterized in peripheral tissues, such as skeletal muscle and fat. However, by acting directly in the hypothalamus, TNFα can activate thermogenesis and modulate food intake. Here we show that high concentration TNFα in the hypothalamus leads to increased O₂ consumption/CO₂ production, increased body temperature, and reduced caloric intake, resulting in loss of body mass. Most of the thermogenic response is produced by β3-adrenergic signaling to the brown adipose tissue (BAT), leading to increased BAT relative mass, reduction in BAT lipid quantity, and increased BAT mitochondria density. The expression of proteins involved in BAT thermogenesis, such as β3-adrenergic receptor, peroxisomal proliferator-activated receptor-γ coactivator-1α, and uncoupling protein-1, are increased. In the hypothalamus, TNFα produces reductions in neuropeptide Y, agouti gene-related peptide, proopiomelanocortin, and melanin-concentrating hormone, and increases CRH and TRH. The activity of the AMP-activated protein kinase signaling pathway is also decreased in the hypothalamus of TNFα-treated rats. Upon intracerebroventricular infliximab treatment, tumor-bearing and septic rats present a significantly increased survival. In addition, the systemic inhibition of β3-adrenergic signaling results in a reduced body mass loss and increased survival in septic rats. These data suggest hypothalamic TNFα action to be important mediator of the wastage syndrome in cachexia.