title: Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency.
abstract: Circulating levels of the cytokine interleukin 18 (IL-18) are elevated in obesity. Here, we show that administration of IL-18 suppresses appetite, feed efficiency, and weight regain in food-deprived male and female C57BL/6J mice. Intraperitoneal vs. intracerebroventricular routes of IL-18 administration had similar potency and did not promote formation of a conditioned taste aversion (malaise-like behavior). Mice partially (Il18(+/-)) or totally (Il18(-/-)) deficient in IL-18 were hyperphagic by young adulthood, with null mutants then becoming overweight by the fifth month of life. Adult Il18(-/-) mice gained 2- to 3-fold more weight than WT mice per unit energy consumed of low- or high-fat diet. Indirect calorimetry revealed reduced energy expenditure in female Il18(-/-) mice and increased respiratory exchange ratios [volume of carbon dioxide production (VCO(2))/volume of oxygen consumption (VO(2))] in mutants of both sexes. Hyperphagia continued in maturity, with overeating greatest during the mid- to late-dark cycle. Relative white fat-pad mass of Il18(-/-) mice was approximately 2- to 3-fold greater than that of WT, with gonadal, mesenteric, and inguinal depots growing most. The data suggest that endogenous IL-18 signaling modulates food intake, metabolism, and adiposity during adulthood and might be a central or peripheral pharmacological target for controlling energy homeostasis.
authors.affiliation: Harold L. Dorris Neurological Research Institute, Committee on the Neurobiology of Addictive Disorders, and Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037, USA. ezorrilla@scripps.edu
authors.forename: Eric P
authors.initials: EP
authors.lastname: Zorrilla
authors.forename: Manuel
authors.initials: M
authors.lastname: Sanchez-Alavez
authors.forename: Shuei
authors.initials: S
authors.lastname: Sugama
authors.forename: Molly
authors.initials: M
authors.lastname: Brennan
authors.forename: Rosette
authors.initials: R
authors.lastname: Fernandez
authors.forename: Tamas
authors.initials: T
authors.lastname: Bartfai
authors.forename: Bruno
authors.initials: B
authors.lastname: Conti
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000367:Age Factors; D000818:Animals; D001066:Appetite / Q000187:drug effects*; D001067:Appetite Depressants; D004435:Eating / Q000187:drug effects*; D002149:Energy Intake / Q000187:drug effects*; D005260:Female; D006706:Homeostasis; D020382:Interleukin-18 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D008297:Male; D008660:Metabolism / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050177:Overweight; D011659:Pulmonary Gas Exchange; D012737:Sex Factors
chemical_list: D001067:Appetite Depressants; D020382:Interleukin-18