Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI؊/؊ mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5-to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese
IL-1RI؊/؊ mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young preobese IL-1RI ؊/؊ mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in preobese IL-1RI ؊/؊ mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity. Diabetes 55: [1205][1206][1207][1208][1209][1210][1211][1212][1213] 2006 T he prevalence of obesity is growing rapidly in many parts of the world and reaching epidemic proportions in several developed countries (1). Overweight and obesity are associated with increased risk of metabolic disorders, such as type 2 diabetes and hyperlipidemia, and thereby increased risk of cardiovascular mortality. Although the regulation of body weight and body composition involves input from lifestyle and environment, compelling scientific evidence indicates that propensity to develop obesity is in large part attributable to genetic factors. Over the last decade, the study of different transgenic and knockout mouse models has contributed to the identification of new factors involved in the complex mechanisms regulating energy balance and to the clarification of the contribution of genetics to obesity (2,3). Moreover, a number of human genes have been identified in which major missense or nonsense mutations as well as genetic variations are associated with obesityrelated phenotypes. Many of these genetic variants have occurred in molecules identical or similar to those identified as a cause of obesity in rodents, supporting their involvement in the regulation of body weight homeostasis also in humans (4).Interleukin-1 (IL-1) is a major mediator of inflammation and exerts effects on the neuro-immuno-endocrine system (5). Infection, injury, and inflammation are associated with negative energy balance, characterized by reduced food intake, weight loss, increased thermogenesis, and fever. IL-1 could be of importance for these effects, as peripheral or central injection of IL-1 induces a marked rise in body temperature (f...