Early data obtained in gene knockout mice indicate that the cytokines IL-6 (1, 2) and interleukin 1β (IL-1β) (3, 4) exert a tonic anti-obesity effect in the CNS, an effect that partly may be due to stimulated thermogenesis and enhanced leptin sensitivity. Therefore, IL-6 and IL-1 seem to exert metabolic effects during health in addition to modulating the immune response during disease. Glucagon-like-peptide-1 (GLP-1) is produced by L-cells in the intestine and in the brainstem. GLP-1analogues are used clinically to enhance insulin secretion from the pancreas, and this way improve glucose metabolism in type 2 diabetes. GLP-1 and its analogues also reduce food intake and body weight, clinically beneficial actions that are likely exerted at the level of the CNS. Recently, we found that central injection of a clinically used GLP-1 receptor agonist, exendin-4, potently increased the expression of IL-6 in the hypothalamus (11-fold), the caudal hindbrain (4-fold) and the parabrachial nucleus (PBN) of the pons. Exendin-4 increased IL-1β expression in the hypothalamus, but not the brainstem or PBN. Exendin-4 treatment did not change the expression of, tumour necrosis factor-alpha TNF-alpha, the third classic pro-inflammatory cytokine, indicating that GLP-1 does not exert a general pro-inflammatory effect (5). Pharmacologic disruption of IL-1 or IL-6 biological activity attenuated anorexia and body weight loss induced by central exendin-4 administration. Simultaneous blockade of IL-1 and IL-6 activity led to a more potent attenuation of exendin-4 effects on food intake. Mice with global IL-1 receptor gene knockout or central IL-6 receptor knockdown showed inhibited decrease in food intake and body weight in response to peripheral exendin-4 treatment. In conclusion . the two cytokines IL-6 and IL-1 exert anti-obesity effect at the level of CNS. They mediate the body weight loss caused by central GLP-1 receptor activation