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Physiological regulation of hypothalamic IL-1 gene expression by leptin and glucocorticoids: implications for energy homeostasis

¹Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Harborview Medical Center, Seattle 98104; ²Department of Medicine, and ³Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, Washington 98108

Submitted 27 January 2004 ; accepted in final form 2 August 2004

Interleukin-1 (IL-1) 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 gene expression is subject to physiological regulation by leptin and glucocorticoids (GCs), key hormones involved in energy homeostasis. Adrenalectomy (ADX) increased hypothalamic IL-1 mRNA levels twofold, measured by real-time PCR (P < 0.05 vs. sham-operated controls), and this effect was blocked by subcutaneous infusion of a physiological dose of corticosterone. Conversely, hypothalamic IL-1 mRNA levels were reduced by 30% in fa/fa (Zucker) rats, a model of genetic obesity caused by leptin receptor mutation (P = 0.01 vs. lean littermates), and the effect of ADX to increase hypothalamic IL-1 mRNA levels in fa/fa rats (P = 0.02) is similar to that seen in normal animals. Moreover, fasting for 48 h (which lowers leptin and raises corticosterone levels) reduced hypothalamic IL-1 mRNA levels by 30% (P = 0.02), and this decrease was fully reversed by refeeding for 12 h. Thus leptin and GCs exert opposing effects on hypothalamic IL-1 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 (2 mg/kg ip) increased hypothalamic IL-1 mRNA levels twofold (P < 0.05 vs. vehicle), an effect similar to that of ADX. These data support a model in which expression of hypothalamic IL-1 is subject to opposing physiological regulation by corticosterone and leptin.

interleukin-1; cytokine; corticosterone; food intake; appetite; obesity; anorexia

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