Physiological regulation of hypothalamic IL-1beta gene expression by leptin and glucocorticoids: implications for energy homeostasis.
Interleukin-1beta (IL-1beta) 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-1beta gene expression is subject to physiological regulation by leptin and glucocorticoids (GCs), key hormones involved in energy homeostasis. Adrenalectomy (ADX) increased hypothalamic IL-1beta 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-1beta 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-1beta 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-1beta 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-1beta 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-1beta 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-1beta is subject to opposing physiological regulation by corticosterone and leptin.
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Harborview Medical Center, 325 Ninth Avenue, Box 359757, Seattle, WA 98104-2499, USA. bewisse@u.washington.edu
Brent E
BE
Wisse
Kayoko
K
Ogimoto
Gregory J
GJ
Morton
Charles W
CW
Wilkinson
R Scott
RS
Frayo
David E
DE
Cummings
Michael W
MW
Schwartz
D000315:Adrenalectomy; D000821:Animal Feed; D000818:Animals; D001835:Body Weight; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D004435:Eating; D004734:Energy Metabolism / Q000502:physiology; D005215:Fasting; D015870:Gene Expression / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D009765:Obesity / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker
D007375:Interleukin-1; D020738:Leptin; D012333:RNA, Messenger; D003345:Corticosterone