The discovery of clock genes revealed the major molecular components responsible for circadian time-keeping in mammals, but the mechanism by which autonomic nervous system may control circadian rhythm and its relationship to metabolism is unclear. As the Cry1 and Cry2 genes are indispensable for molecular core oscillator function, we investigated autonomic nervous system activity and metabolism in Cry1(-/-)Cry2(-/-) mice. The mice were kept in a light-dark cycle, and showed normal circadian locomotor activities including feeding. However, the circadian rhythmicity of oxygen consumption, heart rate, and body temperature were abolished, suggesting hypermetabolism in these mice. Cry1(-/-)Cry2(-/-) mice also showed impaired glucose tolerance due to decreased insulin secretion. These results indicate that sympathetic neural activity in Cry1(-/-)Cry2(-/-) mice is elevated, reducing adiposity and impairing insulin secretion and suggest that dysregulation of the autonomic nervous system may induce metabolic disorders. (C) 2007 Elsevier Inc. All rights reserved.