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.
Wisse
Brent E
BE
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
Ogimoto
Kayoko
K
Morton
Gregory J
GJ
Wilkinson
Charles W
CW
Frayo
R Scott
RS
Cummings
David E
DE
Schwartz
Michael W
MW
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