Adult mice carrying a null mutation of the prostanoid receptor EP3R (EP3R(-/-) mice) exhibit increased frequency of feeding during the light cycle of the day and develop an obese phenotype under a normal fat diet fed ad libitum. EP3R(-/-) mice show increased motor activity, which is not sufficient to offset the increased feeding leading to increased body weight. Altered "nocturnal" activity and feeding behavior is present from a very early age and does not seem to require age-dependent factors for the development of obesity. Obesity in EP3R(-/-) mice is characterized by elevated leptin and insulin levels and >20% higher body weight compared with WT littermates. Abdominal and subcutaneous fat and increased liver weight account for the weight increase in EP3R(-/-) mice. These observations expand the roles of prostaglandin E(2) signaling in metabolic regulation beyond the reported stimulation of leptin release from adipose tissue to involve actions mediated by EP3R in the regulation of sleep architecture and feeding behavior. The findings add to the growing literature on links between inflammatory signaling and obesity.