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The Role of mPer2 Clock Gene in Glucocorticoid and Feeding Rhythms

Laboratory of Biochemical Genetics (S.Y., A.W., M.K.K., J.H.C.), National Heart Lung and Blood Institute, and Developmental Endocrinology Branch (G.A.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Biostatistics and Bioinformatics Branch (A.L.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland 20852; and Program in Human Molecular Biology and Genetics and Division of Endocrinology, Metabolism and Diabetes (R.C.C., D.M., E.D.A.), University of Utah School of Medicine, Salt Lake City, Utah 84112

Address all correspondence and requests for reprints to: Jay H. Chung, M.D., Ph.D., Laboratory of Biochemical Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Building 10-7D14, 10 Center Drive, Bethesda, Maryland 20892. E-mail: chungj{at}nhlbi.nih.gov.

The circadian clock synchronizes the activity level of an organism to the light-dark cycle of the environment. Energy intake, as well as energy metabolism, also has a diurnal rhythm. Although the role of the clock genes in the sleep-wake cycle is well characterized, their role in the generation of the metabolic rhythms is poorly understood. Here, we use mice deficient in the clock protein mPer2 to study how the circadian clock regulates two critical metabolic rhythms: glucocorticoid and food intake rhythms. Our findings indicate that mPer2–/– mice do not have a glucocorticoid rhythm even though the corticosterone response to hypoglycemia, ACTH, and restraint stress is intact. In addition, the diurnal feeding rhythm is absent in mPer2–/– mice. On high-fat diet, they eat as much during the light period as they do during the dark period and develop significant obesity. The diurnal rhythm of neuroendocrine peptide MSH, a major effector of appetite control, is disrupted in the hypothalamus of mPer2–/– mice even though the diurnal rhythm of ACTH, the MSH precursor, is intact. Peripheral injection of MSH, which has been shown to enter the brain, restored the feeding rhythm and induced weight loss in mPer2–/– mice. These findings emphasize the requirement of mPer2 in appetite control during the inactive period and the potential role of peripherally administered MSH in restoring night-day eating pattern in individuals with circadian eating disorders such as night-eating syndrome, which is also associated with obesity.

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