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 ϩ/Ϫ ) 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 (VO2)] 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 Ϸ2-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.obesity ͉ food intake ͉ proinflammatory cytokine ͉ body weight ͉ overweight A pproximately 1 billion people worldwide are overweight or obese, conditions that increase mortality, morbidity, and economic costs (1). Identifying molecular controls of energy homeostasis may inform the etiology or treatment of obesity. Interleukin 18 (IL-18), discovered for its proinflammatory, T cell-polarizing, and IFN-␥-inducing properties (2), shares similarities with IL-1 (3) but acts through its own IL-18 receptor complex (4, 5), a member of the IL-1/Toll-like receptor superfamily. Pro-IL-18 is cleaved on demand by caspase-1 (IL-1 converting enzyme), yielding 18-kDa mature ) and a 35-residue N-terminal fragment (pro-IL-18 ). This posttranslational processing allows regulated release of ''active'' IL-18 from a constitutive intracellular pool of inactive prohormone (6). Like IL-1, IL-18 is a multifunctional polypeptide, with roles in atherosclerosis and myocardial ischemia-reperfusion injury (3).In humans, circulating IL-18 levels directly correlate with body mass index, adiposity, insulin resistance, hypertriglyceridemia, and metabolic syndrome (7-9), consistent with findings that obesity and metabolic syndrome are accompanied by a chronic mild inflammatory state (10). Paradoxically, male IL-18-deficient (Il18 Ϫ/Ϫ ) mice exhibit late-onset obesity (11). A hypothesis to reconcile these findings is that IL-18 is a homeostatic regulator that opposes excess positive energy balance, wherein elevated IL-18 levels in obesity reflect (inadequate) compensation, analogous to what occurs with the adipocytokine leptin. Accordingly, weight loss decreases (12, 13) and hyperglycem...