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Diurnal Rhythm of Agouti-Related Protein and Its Relation to Corticosterone and Food Intake

University of Michigan School of Medicine, Mental Health Research Institute (X.-Y.L., K.-R.S., M.K., H.A., S.J.W.), Ann Arbor, Michigan 48109; and Departments of Pediatrics and Genetics, Howard Hughes Medical Institute, Stanford University (G.S.B.), Stanford, California 94305

Address all correspondence and requests for reprints to: Dr. Xin-Yun Lu, Mental Health Research Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, Michigan 48109-0720. E-mail: xylu{at}umich.edu.

In the present study we examined the diurnal patterns of agouti-related protein (AGRP) and proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus and their relation to circulating glucocorticoids and food intake. Animals were killed at 4-h intervals throughout the 24-h diurnal cycle, and the expression of AGRP and POMC mRNA was evaluated by semiquantitative in situ hybridization analysis. We observed a significant diurnal rhythm in AGRP mRNA expression, with a marked peak at 2200 h (4 h after lights off) and a trough at 1000 h (4 h after lights on), consistent with the overall day-night rhythm of food intake. In contrast, POMC mRNA levels did not show a significant fluctuation across the diurnal cycle, although there was a tendency for levels to decrease after the onset of the dark cycle. Corticosterone secretion temporally coincided with the rising phase of AGRP mRNA expression. Depletion of corticosterone by adrenalectomy abolished the AGRP diurnal rhythm by suppressing the nighttime expression, but did not alter the feeding rhythm. Exposure of adrenalectomized rats to constant corticosterone replacement (10 or 50 mg continuous release corticosterone pellet) resulted in fixed AGRP mRNA expression throughout the 12-h light, 12-h dark cycle. A relatively high level of corticosterone (50 mg) significantly increased AGRP mRNA expression, with a positive correlation between these two measures. These results indicate that 1) the diurnal expression of AGRP mRNA is regulated by corticosterone independently of the light/dark cue; and 2) a normal endogenous corticosterone rhythm is required for generating the diurnal AGRP rhythm.