Interleukin-1 β (IL-1 β) is synthesized in a variety of tissues, including the hypothalamus, where it is implicated in the control of food intake. The current studies were undertaken to investigate whether hypothalamic IL-1 β gene expression is subject to physiological regulation by leptin and glucocorticoids (GCs), key hormones involved in energy homeostasis. Adrenalectomy (ADX) increased hypothalamic IL-1 β mRNA levels, measured by real-time PCR, by two fold (p<0.05 vs. sham-operated controls) and this effect was blocked by sc infusion of a physiological dose of corticosterone. Conversely, hypothalamic IL-1 β mRNA levels were reduced by 30% in fa/fa (Zucker) rats, a model of genetic obesity due to leptin receptor mutation (p=0.01 vs. lean littermates), and the effect of ADX to increase hypothalamic IL-1 β mRNA levels in fa/fa rats (p=0.02) is similar to that seen in normal animals. Moreover, fasting for 48h (which lowers leptin and raises corticosterone levels) reduced hypothalamic IL-1 β mRNA levels by 30% (p=0.02) and this decrease was fully reversed by re-feeding for 12h. Thus, leptin and GCs exert opposing effects on hypothalamic IL-1 β gene expression, and corticosterone plays a physiological role to limit expression of this cytokine in both the presence and absence of intact leptin signaling. Consistent with this hypothesis, systemic leptin administration to normal rats (2mg/kg IP) increased hypothalamic IL-1 β mRNA levels by two fold (p<0.05 vs vehicle), an effect similar to that of ADX. These data support a model in which expression of hypothalamic IL-1 β is subject to opposing, physiological regulation by corticosterone and leptin.