title: Central interleukin-1 (IL1) signaling is required for pharmacological, but not physiological, effects of leptin on energy balance.
abstract: Hypothalamic IL1 is suggested to be a critical mediator of the central effects of the adipocyte hormone leptin on energy balance. We hypothesized that IL1 receptor signaling is required for exogenously administered leptin to cause anorexia and weight loss, but not for physiological effects of endogenous leptin signaling on energy balance. To test this hypothesis, we investigated whether chronic hypothalamic over-expression of an IL1 receptor antagonist (AdV-IL1ra) alters food intake and weight gain in normal rats. Our findings demonstrate that impaired IL1 signaling in the CNS did not cause excess weight gain over a period of 11 days (AdV-IL1ra +38.1+/-4.1 g vs. VEH +42.2+/-5.6g; p=0.6) and caused a slightly reduced daily food intake (AdV-IL1ra 29.0+/-1.1 g/day vs. VEH 33.0+/-1.6 g/day; p<0.05). Blocking central IL1 signaling also did not alter the re-feeding response to a prolonged fast, yet was entirely effective in preventing the anorexic effect of exogenously administered leptin (2 mg/kg ip, cumulative food intake at 18 h AdV-IL1ra 30.5+/-1.1 g vs. VEH 26.4+/-1.7 g, p<0.05) and prevented leptin-induced weight loss (AdV-IL1ra -0.1+/-1.3 g vs. VEH -2.7+/-1.9 g, p<0.05). Together these findings suggest that hypothalamic IL1 signaling is required for the pharmacological effects of leptin administration, but that impaired hypothalamic IL1 signaling does not alter the physiological regulation of energy balance.
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, WA 98108, USA. bewisse@u.washington.edu
authors.forename: Brent E
authors.initials: BE
authors.lastname: Wisse
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ogimoto
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.forename: Diana L
authors.initials: DL
authors.lastname: Williams
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
mesh_terms: D000256:Adenoviridae / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight / Q000187:drug effects; D002490:Central Nervous System / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005215:Fasting / Q000502:physiology; D007375:Interleukin-1 / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D007375:Interleukin-1; D020738:Leptin